SUBSTITUTED ALICYCLIC AMINE-CONTAINING MACROCYCLIC IMMUNOMODULATORS

Abstract: Compounds having formula (I), and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein one of R<104> and R<105> is hydrogen, and the other of R<104> and R<105> is a group having formula (II), as well as pharmaceutically compositions containing such compounds and methods of immunomodulative therapy utilizing the same.

Description: SUBSTTTUTED ALICYCLIC AMINE-CONTAINING MACROCYCLIC IMMUNOMODULATORS This application is a continuation-in-part of the copending United States patent application Serial No. 08/032,958, filed on March 17, 1993. Field of the Invention The present invention relates to novel chemical compounds having immunomodulatory activity, and in particular to macrolide immunosuppressants. More particularly, the invention relates to semisynthetic analogs of ascomycin and FK-506, means for their preparation, pharmaceutical compositions containing such compounds and methods of treatment employing the same. Background of the Invention The compound cyclosporine (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures. Unsatisfactory side- effects associated with cyclosporine, however, such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved efficacy and safety. Recently, several classes of macrocyclic compounds having potent immunomodulatory activity have been discovered. Okuhara etal., in European Patent Application No. 184162, published June 11, 1986, disclose a number of macrocyclic compounds isolated from the genus Streptomyces. Immunosuppressant FK-506, isolated from a strain of S. tsukubaensis , is a 23-membered macrocyclic lactone represented by formula la, below. Other related natural products, such as FR-900520 (lb) and FR-900523 (lc), which differ from FK-506 in their alkyl substituent at C-21, have been isolated from S. hygroscopicus yakushimnaensis. Yet another analog, FR-900525, produced by S. tsukubaensis, differs from FK-506 in the replacement of a pipecolic acid moiety with a proline group. FR-900520, also known as ascomycin, has been previously disclosed by Arai et al. in U.S. Patent No. 3,244,592, issued April 5, 1966, where the compound is described as an antifungal agent Monaghan, R.L., et al ., on the other hand, describe the use of ascomycin as an immunosuppressant in European Patent Application No. 323865, published July 12, 1989. Although the immunosuppressive activity of FK-506 has been clinically confirmed, toxicity in mammals has limited its utility. The activity of FK-506 has, however, prompted efforts to discover novel analogs of FK-type compounds which possess superior properties. These efforts include the isolation of new fermentation products, the microbial transformation of existing chemical entities, the chemical modification of these macrocycles, and the synthesis of hybrid species derived from smaller synthetic fragments. 1(a): FK-506 R = CH 2 CH=CH 2 ; n=l 1(b): FR-900520 R = CH 2 CH 3 ; n=l 1(c): FR-900523 R = CH3; n=l 1(d): FR-900525 R = CH 2 CH=CH 2 ; n=0 Fermentation products of FK-type compounds include C-21-epi derivatives of FK-506; a 31-demethylated derivative of FK-506; 31-oxo-FK-506; and compounds derived from FK-506, FR-900523 and FR-900525 which are characterized by the introduction of hydroxy- protecting groups, formation of a double bond by elimination of water between carbons 23 and 24, oxidation of the hydroxy group at carbon 24 to the ketone, and reduction of the allyl side- chain at carbon 21 via hydrogenation. Other published derivatives include those derived from FK-506 and FR-900520 where the lactone ring is contracted to give a macrocyclic ring containing two fewer carbons. Several microbial transformations of FK-type compounds at carbon 13 have been published, such as the microbial demethylation of FR-900520 to form the bw-demethylated 13,31-dihydroxy ring-rearranged derivative of FR-900520; the microbial monodemethylation of FK-506 and FR-900520, respectively; and the microbial demethylation of FR-900520 at C- 31, as well as a number of other macrocyclic microbial transformation products. Numerous chemical modifications of the FK-type compounds have been attempted. These include the preparation of small synthetic fragments of FK-type derivatives; a thermal rearrangement of a variety of derivatives of FK-506 which expands the macrocyclic ring by two carbons; and modifications which include methyl ether formation at C-32 and/or C-24, oxidation of C-32 alcohol to the ketone, and epoxide formation at C-9. Although some of these modified compounds exhibit immunosuppressive activity, the need remains for macrocyclic immunosuppressants which do not have the serious side effects frequently associated with immunosuppressant therapy. Accordingly, one object of the invention is to provide novel semisynthetic macrolides which possess the desired immunomodulatory activity but which may be found to minimize untoward side effects. Another object of the present invention is to provide synthetic processes for the preparation of such compounds from starting materials obtained by fermentation, as well as chemical intermediates useful in such synthetic processes. A further object of the invention is to provide pharmaceutical compositions containing, as an active ingredient, one of the above compounds. Yet another object of the invention is to provide a method of treating a variety of disease states, including post-transplant tissue rejection and autoimmune disfunction. Summary of the Invention In one aspect of the present invention are disclosed compounds having the formula and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein RIOO i s hydrogen, hydroxy, halogen, -OR 3 or -ORl4; RIO* is methyl, ethyl, allyl or propyl; R 102 i s hydrogen and Rl03 s selected from (a) hydrogen, (b) hydroxyl and (c) hydroxyl protected by a hydroxy-protecting group or, taken together, Rl02 and R*03 f orm a bond; and one of R 104 and Rl05 is hydrogen, and the other of R 104 a nd R 05 i s a group having the formula where m and n are independently zero, one or two; X is selected from the group consisting of oxygen, -S(O) s - where s is zero, one or two, -NCR 1 )- and -C(R 2 )(R 2' )-, or is absent; and R3, R4 and R^ are independently selected from the group consisting of (a) hydrogen; (b) alkyl; (c) haloalkyl; (d) cycloalkyl; (e) cycloalkylalkyl; (f) alkenyl; (g) alkynyl; (h) hydroxyalkyl; (i) hydroxylalkoxyalkyl; (j) aryl substituted by R \ R? and R^; (j') arylalkyl substituted by R^, R7 and R* ; (k) alkoxycarbonyl; (1) alkoxycarbonylalkyl; (m) carboxyalkyl; (n) aminoalkyl; (o) thiolalkyl; (q) heterocyclic; (r) (heterocyclic)alkyl; (s) (heterocyclic)alkyl- aminoalkyl; (p) acyl; (u) N-mono- or N,N-dialkylaminoalkyl; (v) N-mono- or N,N-dialkyl- carboxamidoalkyl; (w) N-mono- or N,N-diarylcarboxamidoalkyl; (x) formyl; (x 1 ) protected formyl; (z) (heterocyclic)alkenyl; and (aa) (heterocyclic)alkynyl. Alternatively, R^ and R^, when taken together, may form a methylene -CH - so that the group of Formula (II) becomes a bicyclic radical. In the above, R 1 is selected from the group consisting of (a) hydrogen; (b) alkyl; (c) haloalkyl; (d) cycloalkyl; (e) cycloalkylalkyl; (f) alkenyl; (g) alkynyl; (h) hydroxyalkyl; (i) hydroxylalkoxyalkyl; (j) aryl substituted by R^, R^ and R^; (j') arylalkyl substituted by R^, R7 and R^; (k) alkoxycarbonyl; (1) alkoxycarbonylalkyl; (m) carboxyalkyl; (n) aminoalkyl; (o) thiolalkyl; (p) -S(O) x -R 9 , wherein x is one or two and R^ is selected from the group consisting of alkyl, aryl, and arylalkyl; (q) heterocyclic; (r) (heterocyclic)alkyl; (s) (heterocyclic)alkylaminoalkyl; (t) acyl; (u) N-mono- orNN-dialkylaminoalkyl; (v) N-mono- or N,N-dialkylcarboxamidoalkyl; (w) N-mono- or N,N-diarylcarboxamidoalkyl; (x) formyl; (x') protected formyl; (y) -P(O)(OR 10 )(OR 10' ) where R 10 and R 10 ' are independently selected from the group consisting of loweralkyl, arylalkyl and aryl; (z) (heterocyclic)alkenyl; (aa) (heterocyclic)-alkynyl; (bb) urea; (cc) nitro; and (dd) polyhydroxylalkyl. R 2 and R 2 ' in the above are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amidoalkyl, N-alkylcarboxamido, N,N-dialkylamino, and -(CH2) m '-Ν where m' is four or five; or, taken together, R 2 and R 2' are oxo, thiooxo or -O(CH 2 )iO-, where i is two, three or four. R6, R7 and R * in the above are independently selected from (i) hydrogen; (ϋ) -(Ci-to- C7 alkyl); (iii)-(C 2 -to-C6 alkenyl); (iv) halogen; (v) -(CH^m R^R 11' where m is an integer between one and ten, inclusive, and R 11 and R 11' are independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, (heterocyclic)alkenyl and (heterocyclic)alkynyl; (vi) -CN; (vii) -CHO; (viii) mono-, di-, tri- or perhalogenated alkyl; (ix) -SCO^R 11 where s is zero, one or two; (x) -C^NR^R 11' ; (xi) -(CH 2 ) m OR n ; (xii) -CH(OR 12 )(OR 12' ), where R 12 and R 12' are independently -(CH0-C3 alkyl) or, taken together, form an ethylene or propylene bridge; (xiii) -(CH 2 ) m OC(O)R 11 ; (xiv) -(CH^mC^OR 11 ; (xv) -OR 13 ; (xvi) -S(O) t NR 11 R 11' , where t is one or two; (xvii) -NO 2 ; (xviii) -N 3 ; and (xviv) guanidino optionally substituted by a radical selected from the group consisting of loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and alkylsulfonyl. Alternatively, any two adjacent R 6 , R 7 and R 8 and the atoms to which they are attached may form a carbocyclic or heterocyclic ring having 5, 6 or 7 ring atoms which optionally include one or two additional heteroatoms independently selected from the group consisting of -O-, -S(O) s - where s is zero, one or two, and -NR 11 -. R 13 in the above is selected from (i) -PO(OH)O"M + , (ϋ) -SO3'M + , and (ϋi) -C(0XCH 2 ) m C(0)0"M + , where M + is a proton or a positively charged inorganic or organic counterion, and m is an integer between one and ten, inclusive. R 14 in the above is selected from the group consisting of (i) acyl ; (ϋ) -(CH0-C7 alkyl); (ϋi) -(C 2 -to-C6 alkenyl); (vi) -(CH^mNR^R 11 ', where m is an integer between one and ten, inclusive; (v) -S(O) s R 11 , where s is zero, one or two; (vi) (x) -(CH 2 ) m C(O)OR n ; and (xi) -S^ t NR^R 11' , where t is one or two; In another aspect of the present invention are disclosed pharmaceutical compositions, comprising a compound of the invention in combination with a pharmaceutically acceptable carrier. In a further aspect of the present invention is disclosed a method for treating a patient in need of immunomodulative therapy, comprising administering to such a patient a therapeutically effective amount of a compound of the invention for such time as is necessary to obtain the desired therapeutic effect Detailed Description of the Invention Among the preferred compounds of the present invention are those having formula (I) in which: m and n are independently zero or one; X is selected from the group consisting of -S(O) s - and -NQil 1 )-; and/or R 1 , R 3 , R 4 and R 5 are independently selected from the group consisting of (a) hydrogen; (b) alkyl; (c) cycloalkyl; (d) cycloalkylalkyl; (e) hydroxyalkyl; (f) hydroxyl¬ alkoxyalkyl; (g) aryl substituted by R^, R7 and R 8 ; (h) arylalkyl substituted by R 6 , R 7 and R 8 ; (i) alkoxycarbonyl; (j) alkoxycarbonylalkyl; (k) carboxyalkyl; (1) aminoalkyl; (m) thiolalkyl; (n) heterocyclic; (o) (heterocyclic)alkyl; (p) (heterocyclic)alkylaminoalkyl; (q) acyl; (r) N-mono- or N,N-dialkylaminoalkyl; (s) N-mono- or NN_ -dialkyl- carboxamidoalkyl; (t) N-mono- or NN-diarylcarboxamidoalkyl; and (u) formyl. Also preferred are those compounds in which X in the heterocyclic ring of formula (II) is selected from the group consisting of -NCR 1 )- and -C(R 2 )(R 2 ')-, and the total of m and n is zero, one or two (that is, where the heterocycle is a 5- to 7-membered ring). Representative of the compounds of the present invention are those which are demonstrated in Examples 5, 7, 9, 11-22, 27, 28, 31, 38, 39, 44, 58, 61, 62, 67, 76 and 105-111, below. The most preferred of these compounds, and that contemplated as the best mode thereof, is the compound described in Example 17 hereof. As used throughout this specification and in the appended claims, the following terms have the meanings specified: The term "acyl" as used herein refers to an aryl or alkyl group, as defined below, appended to a carbonyl group including, but not limited to, acetyl, pivaloyl, benzoyl and the like. The term "alkenyl" as used herein refers to straight or branched chain groups of 2 to 12 carbon atoms containing a carbon-carbon double bond including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. The terms "alkoxy" as used herein refer to a loweralkyl group, as defined below, attached to the remainder of the molecule through an oxygen atom including, but not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, _sec-butoxy, isobutoxy, tert-butoxy and the like. The terms, "alkoxyalkyl" as used herein refers to an alkoxy group, as defined above, appended to an alkyl group including, but not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, i-propyloxymethyl, n-butoxyethyl and the like. The term "alkoxycarbonyl" as used herein refers to an alkoxy group, as defined above, attached via a carbonyl group including, but not limited to, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, cyclohexyloxycarbonyl and the like. The term "alkoxycarbonylalkyl" as used herein refers to an alkoxycarbonyl group, as defined above, attached via an alkyl group including, but not limited to, methyloxycarbonylmethyl, ethyloxycarbonylethyl, tert-butyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl and the like. The term "alkyl" as used herein refers to a monovalent straight chain or branched chain group of 1 to 12 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like. The terms "alkylamino" and "loweralkylamino" as used herein refer to a group having the structure -NH-(loweralkyl), where the loweralkyl portion is as defined below. Alkylamino and loweralkylamino groups include, for example, methylamino, ethylamino, isopropylamino and the like. The term "alkylsulfonyl" as used herein refers to an alkyl group, as defined above, attached via a sulfur dioxide diradical including, but not limited to, methanesulfonyl, camphorsulfonyl and the like. The terms "alkylthioether", "thioalkoxy" and "thioloweralkoxy" as used herein refer to a loweralkyl group, as previously defined, attached via a sulfur atom including, but not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, sec-thiobutoxy, isothiobutoxy, tert-thiobutoxy and the like. The term "alkynyl" as used herein refers to straight or branched chain groups of 2 to 12 carbon atoms containing a carbon-carbon triple bond including, but not limited to acetylenyl, propargyl and the like. The term "amidoalkyl" as used herein refers to a group having the structure -N(R401)C(O)R402 appended to a loweralkyl group, as previously defined. The groups R401 and R402 are independently selected from hydrogen, lower alkyl, aryl, arylalkyl, and halosubstituted alkyl. Alternatively, R401 and R402, taken together, may be -(CH 2 )aa- where aa is an integer of from two to six. The term "aminoalkyl" as used herein refers to a group having the structure -NR403R404 appended to a loweralkyl group, as previously defined. The groups R403 and R404 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl. Alternatively, R403 and R404, taken together, may be -(CH 2 ) bb - where bb is an integer of from two to six. The terms "aryl" as used herein refers to carbocyclic aromatic groups including, but not limited to, phenyl, 1- or 2-naphthyl, fluorenyl, (1, 2)-dihydronaphthyl, (l,2,3,4)-tetrahydro- naphthyl, indenyl, indanyl and the like. The terms "arylalkoxy" and "arylalkylether" as used herein refer to an arylalkyl group, as defined below, attached to the parent molecular moiety through an oxygen atom. Arylalkoxy includes, but is not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy and the like. The term "arylalkoxycarbonyl" as used herein refers to an arylalkoxy group, as defined above, attached via a carbonyl group including, but not limited to, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and the like. The term "arylalkyl" as used herein refers to an aryl group, as previously defined, appended to an alkyl group including, but not limited to, benzyl, 1- and 2-naphthylmethyl, halobenzyl, alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidinobenzyl, fluorenyknethyl, phenylmethyl(benzyl), 1 -phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like. The terms "arylether" and "aryloxy" as used herein refer to an aryl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Aryloxy and arylether include, but are not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy and the like. The term "aryloxycarbonyl" as used herein refers to an aryloxygroup, as defined above, attached via a carbonyl group including, but not limited to, phenyloxycarbonyl. The term "aryloxycarbonylamino" as used herein refers to an aryloxycarbonyl group, as defined above, appended to an amino group including, but not limited to, phenyloxycarbonylamino. The term "arylsulfonyl" as used herein refers to an aryl group, as defined above, attached via a sulfur dioxide diradical including, but not limited to p-toluenesulfonyl, benzenesulf onyl and the like. The terms "arylthioether" and "thioaryloxy" as used herein refer to an aryl group, as defined above, attached via a sulfur atom. The term "carboxamido" as used herein refers to an amino group attached via a carbonyl group and having the formula -C(O)NH . The term "carboxyalkyl" as used herein refers to a carboxyl group, -CC^H, appended to a loweralkyl group, as previously defined. The term "cycloalkenyl" as used herein refers to a cyclic group of 5 to 10 carbon atoms possessing one or more carbon-carbon double bonds including, but not limited to, cyclopentenyl, cyclohexenyl and the like, in which the point of attachment can occur at any available valency on the carbocylic ring. The term "cycloalkyl" as used herein refers to a cyclic group of 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkylalkenyl" as used herein refers to a cycloalkyl group, as defined above, appended to an alkenyl group, as defined above. The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a lower alkyl group including, but not limited to, cyclohexylmethyl and cyclohexylethyl. The term "cycloalkylalkynyl" as used herein refers to cycloalkyl, as defined above, appended to an alkynyl group, as defined above. The term "guanidinoalkyl" as used herein refers to a group of the structure -N(R405)C(=NR406)NHR407 appended to a loweralkyl group, as previously defined. R405, R406 and R407 are independently selected from hydrogen, lower alkyl, heterocyclic, aminoalkyl and aryl. Alternatively, R406 and R407, taken together, may be -(CH 2 ) CC - where cc is an integer of from two to six. The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine. The terms "haloalkyl" as used herein refer to halogen appended to an alkyl group, as previously defined. The term "heterocyclic" as used herein, except where otherwise specified, refers to any aromatic or non-aromatic 5-, 6- or 7-membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized by unsaturation and/or substitution by hydroxy, thiol, oxo or thiooxo, (ϋi) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above heterocyclic rings may be fused to a benzene ring. Representative heterocycles include, but are not limited to, pyrrolyl, pyrroϋdinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl, imidazoϋdinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracϋyl, isoxazolyl, isoxazoϋdinyl, morpholinyl, indolyl, quinolinyl, uracϋyl, urazolyl, uricyl, thiazolyl, thiazoϋdinyl, isothiazolyl, isothiazoϋdinyl, isoquinolinyl, thyminyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl. The term "(heterocycϋc)alkyl" as used herein refers to a heterocycϋc group appended to an alkyl group, as previously defined. The term "(heterocycϋc)alkylaminoalkyl" as used herein refers to a (heterocycϋc)alkyl group appended to an aminoalkyl group, as previously defined. The term "(heterocydic)alkylether" as used herein refers to a (heterocycϋc)alkyl moiety, as defined above, attached via an oxygen atom. The term "(heterocyclic)alkenyl" as used herein refers to a heterocycϋc group appended to an alkenyl group, as previously defined. The term "(heterocyclic)alkylthioether" as used herein refers to a (heterocycϋc)alkyl moiety, as defined above, attached via a sulfur atom. The term "(heterocyclic)alkynyl" as used herein refers to a heterocydic group appended to an alkynyl group, as previously defined. The term "(heterocyclic)ether" as used herein refers to a heterocycUc moiety, as defined above, attached via an oxygen atom. The term "(heterocydic)thioether" as used herein refers to a heterocyclic moiety, as defined above, attached via a sulfur atom. The terms "hydroxyalkyl" as used herein refer to -OH appended to a loweralkyl group, as defined below. The terms "hydroxyalkyloxyalkyl" as used herein refer to -OH appended to an alkyloxyalkyl group, as defined above. The term "hydroxy-protecting group" as used herein refers to those groups which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable including, but not limited to, dimethylthexylsϋyl, trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsUyl, triethylsilyl, tributylsUyl, tri-i-propylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsϋyl, triphenylmethyl-dimethylsilyl, etc.); lower alkyldiarylsϋyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsϋyl, propyl-diphenylsϋyl, tert-butyl-diphenylsϋyl, etc.), and the like; triarysilyl (e.g. triphenylsilyl, tri-p-xylylsϋyl, etc.); triarylalkylsUyl (e.g. tribenzylsilyl, etc.), acyl substituted with an aromatic group and the like. Other classes of hydroxy-protecting group which may be useful include, but are not limited to, chlorocarbonate analogues such as trimethylsϋylethoxycarbonyl, methylthiomethoxyethoxy- carbonyl or benzenesulfonylethoxycarbonyl; trimethylsUylethoxymethyl, and the like, The term "loweralkyl" as used herein refers to an alkyl group, as defined above, of 1 to 8 carbon atoms. The terms "monoalkylamino" and "dialkylamino" refer respectively to one and two alkyl or cycloalkyl groups, as defined above, appended to an amino group including, but not limited to, methylamino, isopropylamino, cyclohexylamino, dimethylamino, N,N-methytisopropylamino; bw-(cyclohexyl)amino and the like. The term "N-alkylcarboxamido" as used herein refers to an alkylamino group, as defined above, attached via a carbonyl group and having the formula HN(alkyl)C(O)-. The term "N-arylcarboxamido" as used herein refers to an arylamino group, as defined above, attached via a carbonyl group and having the formula HN(aryl)C(O)-. The term "N,N-dialkylcarboxamido" as used herein refers to an amino group substituted with two alkyl groups, as defined above, wherein the two alkyl groups need not be identical, attached via a carbonyl group and having the formula N(alkyl)(alkyr)C(O)-. The term "N,N-diarylcarboxamido" as used herein refers to an amino group substituted with two aryl groups, as defined above, wherein the two aryl groups need not be identical, attached via a carbonyl group and having the formula N(aryl)(aryr)C(O)-. The term "N-alkylcarboxamidoalkyl" as used herein refers to an alkylcarboxamido group, as defined above, attached via an alkyl group and having the formula HN(alkyl)C(O)- alkyl-. The term "N-arylcarboxamidoalkyl" as used herein refers to an arylcarboxamido group, as defined above, attached via an alkyl group and having the formula HN(aryl)C(O)-alkyl-. The term "N.N-dialkylcarboxamidoalkyl" as used herein refers to an amino group substituted with two alkyl groups, as defined above, wherein the two alkyl groups need not be identical, attached via a carbonyl group and having the formula N(alkyl)(alkyl')C(O)-alkyl-. The term "N,N-diarylcarboxamido" as used herein refers to an amino group substituted with two aryl groups, as defined above, wherein the two aryl groups need not be identical, attached via a carbonyl group and having the formula N(aryl)(aryl')C(O)-alkyl-. The term "oxo" as used herein refers to an oxygen atom forming a carbonyl group. The term "polyhydroxyalkyl" as used herein refers to two or more hydroxyl groups appended to an alkyl group, as defined above. The term "protected formyl group" as used herein refers to those groups which are known in the art to protect a formyl group against undesirable reaction during synthetic procedures and to be selectively removable including, but not limited to, dimethyl acetal, diethyl acetal, bw(2,2,2-trichloroethyl) acetals, Dibenzyl acetal, 1,3-dioxane, 5-methylene- 1,3-dioxane, 5,5-dibromo-l,3-dioxane, O-methyl-S-2-(methylthio)ethyl acetal, 1,3-oxathiolanes and the like. The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group, as defined above, appended to a loweralkyl group. The term "thioalkyl" as used herein refers to an alkyl group, as defined above, attached via a sulfur atom. The term "thiooxo" as used herein refers to a sulfur atom forming a thiocarbonyl group. The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non- toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts." J. Pharm. Sci.. 66:1-19 (1977) which is incorporated herein by reference.) Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include Ci-to- alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include Cs-to-C cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. Cχ-to-C 4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods. Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci-to-Cg alkyl amines and secondary Ci-to-Cβ dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Cι-to-C3 alkyl primary amides and Cι-to-C 2 dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. Where appropriate, prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method. For those compounds in which the prodrug moiety is an amino acid or peptide functionality, the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodϋmede) method, the active ester method (p-nitrophenyl ester method, N- hydroxysuccinic acid imide ester method, cyanomet yl ester method and the like), the Woodward reagent K method, the DCC- HOBT (1-hydroxy-benzotriazole) method and the like. Classical methods for amino acid condensation reactions are described in "Peptide Synthesis" Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976). As in conventional peptide sysnthesis, branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary. The protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chlorobenzyloxycarbonyl ((2-Cl)Z)), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfonyl (Nps), diphenylphosphinothioyl (Ppt) and dimethylphosphino-thioyl (Mpt). The examples for protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and the like. In the course of the synthesis of certain of the compounds of the present invention, specific amino acids having functional groups other than amino and carboxyl groups in the branched chain such as arginine, cysteine, serine and the like may be protected, if necessary, with suitable protecting groups. It is preferable that for example, the guanidino group (NG) in arginine may be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-dimethyl- benzenesulfonyl (Mts) and the like; the thiol group in cysteine may be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6-trimethylbenzyl (Tmb) and the like; and the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (TOP) and the like. Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy Une, it is intended that both steric orientations are intended. It should also be noted that certain variable elements of the structural formulae herein, such as the radicals R 11 and R 12 or the integers m, s and t, may appear more than once in a particular formula. In such instances, it is intended that, within a single formula, the values of these variables may be the same or different at each occurrence. The compounds of the invention, including but not limited to those specified in the examples, possess immunomodulatory activity in animals. As immunosuppressants, the compounds of the present invention may be useful for the treatment and prevention of immune- mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, hver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.; graft- versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, allergic encephalomyelitis, glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms. Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vascuUtides, erythemas, cutaneous eosinophiϋas, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epitheliaϋs corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; reversible obstructive airway disease, which includes condition such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis and the like; inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocoϋtis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases; intestinal inflammations/allergies such as Coeϋac diseases, proctitis, eosinophϋic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases which have symptomatic manifestation remote from the gastro¬ intestinal tract (e.g. migraine, rhinitis and eczema); renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guϋlain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, as for example organ injury such as ischemia-reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic disease (for example, thrombosis and cardiac infraction): intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency; pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn; dermatitis such as erythema multiforme, ϋnear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C4 release; Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. Furthermore, the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune ϋver diseases such as the group consisting of autoimmune hepatitis, primary bitiary cirrhosis and sclerosing cholangitis), partial ϋver resection, acute ϋver necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (such as alcohoϋc cirrhosis) and hepatic faϋure such as fulminant hepatic faϋure, late-onset hepatic failure and "acute-on-chronic" Uver faϋure (acute ϋver failure on chronic ϋver diseases), and moreover are useful for various diseases because of their useful activity such as augmention of chemotherapeutic effect preventing or treating activity of cytomegalovirus infection, particularly HCMV infection, anti- inflammatory activity, and so on. Additionally, some compounds appear to possess FK-506 antagonistic properties. The compounds of the present invention may thus be used in the treatment of immunodepression or a disorder involving immunodepression. Examples of disorders involving immunodepression include AIDS, cancer, senUe dementia, trauma (including wound healing, surgery and shock) chronic bacterial infection, and certain central nervous system disorders. The immunodepression to be treated may be caused by an overdose of an immunosuppressive macrocycϋc compound, for example derivatives of 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-l l,28-dioxa-4-azatricyclo[22.3.1.04.9] octacos-18-ene such as FK-506, or rapamycin. Overdosing of such medicants by patients is quite common upon their realizing that they have forgotten to take their medication at the prescribed time and can lead to serious side effects. The compounds of the present invention may also find utiϋty in the chemosensitization of drug resistant target cells. Cyclosporin A and FK-506 are known to be effective modulators of P-glycoprotein, a compound which binds to and inhibits the action of anticancer drugs; by inhibiting P-glycoprotein, they are capable of increasing the sensitivity of multidrug resistant (MDR) ceϋs to chemotherapeutic agents. It is beϋeved that the compounds of the invention may likewise be effective at overcoming resistance expressed to clinicaϋy useful antitumour drugs such as 5-fluorouraril, cisplatin, methotrexate, vincristine, vinblastine and adriamycin, colchicine and vincristine. A further situation in which the compounds of the present invention may be used to treat immunosuppression is in vaccination. It is sometimes found that the antigen introduced into the body for the acquisition of immunity from disease acts as an immunosuppressive agent and so antibodies are not produced by the body and immunity is not acquired. By introducing a compound of the invention into the body (as in a vaccine), the undesrred immunosuppression may be overcome and immunity acquired. Aqueous ϋquid compositions of the present invention may be particularly useful for the treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, dysophia epitheliaϋs corneae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of corneal transplantation. When used in the above or other treatments, a therapeuticaUy effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist in pharmaceuticaUy acceptable salt, ester or prodrug form. Alternatively, the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceuticaUy acceptable excipients. By a "therapeuticaUy effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat gastrointestinal disorders, at a reasonable benefit/risk ratio applicable to any medical treatment It wiU be understood, however, that the total daϋy usage of the compounds and compositions of the present invention wiU be decided by the attending physician within the scope of sound medical judgement. The specific therapeuticaUy effective dose level for any particular patient wiU depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors weU known in the medical arts. For example, it is well within the skiU of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to graduaUy increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.001 to about 3 mg/kg/day. For purposes of oral administration, more preferable doses may be in the range of from about 0.005 to about 1.5 mg kg/day. If desired, the effective daily dose may be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. The pharmaceutical compositions of the present invention comprise a compound of the invention and a pharmaceuticaUy acceptable carrier or excipient, which may be administered oraUy, rectally, parenteraϋy, intracisternally, intravaginally, intraperitoneaUy, topically (as by powders, ointments, drops or transdermal patch), bucaUy, or as an oral or nasal spray. By "pharmaceuticaUy acceptable carrier" is meant a non-toxic soϋd, semi-soϋd or Uquid fiUer, dϋuent, encapsulating material or formulation auxiϋary of any type. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as weU as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, dϋuents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylceUulose and suitable mixtures thereof, vegetable oϋs (such as oϋve oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a Uquid suspension of crystaUine or amorphous material with poor water solubϋity. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystaUine form. Alternatively, delayed absorption of a parenteraUy administered drug form is accompϋshed by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycoUde. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be steriϋzed, for example, by filtration through a bacterial-retaining filter, or by incorporating steriϋzing agents in the form of sterile soϋd compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Sotid dosage forms for oral administration include capsules, tablets, piUs, powders, and granules. In such soϋd dosage forms, the active compound is mixed with at least one inert, pharmaceuticaUy acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fiUers or extenders such as starches, lactose, sucrose, glucose, mannitol, and siϋcic acid, b) binders such as, for example, carboxymethylceUulose, alginates, gelatin, polyvinylpyrroϋdone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain siϋcates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaoϋn and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, soϋd polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and piUs, the dosage form may also comprise buffering agents. Soϋd compositions of a simUar type may also be employed as fiUers in soft and hard- fiUed gelatin capsules using such excipients as lactose or milk sugar as weU as high molecular weight polyethylene glycols and the like. The soϋd dosage forms of tablets, dragees, capsules, piUs, and granules can be prepared with coatings and sheUs such as enteric coatings and other coatings weU known in the pharmaceutical formulating art They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionaUy, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceuticaUy acceptable emulsions, solutions, suspensions, syrups and eϋxirs. In addition to the active compounds, the Uquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubiϋzing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oϋs (in particular, cottonseed, groundnut, com, germ, oϋve, castor, and sesame oϋs), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert dϋuents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical administration, including those for inhalation, may be prepared as a dry powder which may be pressurized or non-pressurized. In non- pressurized powder compositions, the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceuticaUy acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter. Suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers. Alternatively, the composition may be pressurized and contain a compressed gas, such as nitrogen or a Uquified gas propeUant The Uquified propeUant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surface active agent. The surface active agent may be a Uquid or soϋd non-ionic surface active agent or may be a soϋd anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt. A further form of topical administration is to the eye, as for the treatment of immune- mediated conditions of the eye such as automimmue diseases, aUergic or inflammatory conditions, and corneal transplants. The compound of the invention is deUvered in a pharmaceuticaUy acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to aUow the compound to penetrate the corneal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and sclera. The pharmaceuticaUy acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are soϋd at room temperature but Uquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Compounds of the present invention can also be administered in the form of Uposomes. As is known in the art, Uposomes are generally derived from phospholipids or other Upid substances. Liposomes are formed by mono- or multi-lameUar hydrated Uquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologicaUy acceptable and metaboϋzable Upid capable of forming Uposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabiϋzers, preservatives, excipients, and the like. The preferred Upids are the phosphoϋpids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XTV, Academic Press, New York, N.Y. (1976), p. 33 et seq. The compounds of the invention may be prepared using one or more of the processes which foUow. The starting materials for use in these processes are preferably one of the macrotides isolated from culture media obtained in accordance with known methods by fermentation of microorganisms of the genus Strep tomvces. which are disclosed in European Patent Application No. 0184162. Samples are available from the Fermentation Research Institute, Tsukuba, Ibaraki 305, Japan under the provisions of the Budapest Treaty, under deposit No. FERM BP-927. This strain has been redeposited on April 27, 1989 with the Agricultural Research Culture Collection International Depository, Peoria, IUinois 61604, USA under the provisions of the Budapest Treaty, under deposit No. NRRL 18488. The macrolide FR-900520 (European Patent Application 0184162), also known as ascomycin, may be prepared in accordance to the published methods of (i) H. Hatanaka, M. Iwami, T. Kino, T. Goto and M. Okuhara, FR-900520 and FR-900523, Novel immunosuppressants isolated from A streptomyces. I. Taxonomy of the producing strain. J. Antibiot., 1988. XLI(11), 1586- 1591; (ii) H. Hatanaka, T. Kino, S. Miyata, N. Inamura, A. Kuroda, T. Goto, H. Tanaka and M. Okuhara, FR-900520 and FR-900523 , Novel immunosuppressants isolated from A streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics. J. Antibiot., 1988. XLI(ll), 1592-1601; (iii) T. Arai, Y. Koyama, T. Suenaga and H. Honda, Ascomycin, An Antifungal Antibiotic. J. Antibiot., 1962. 15(231-2); and (iv) T. Arai in U.S. Patent No. 3,244,592. One or more of the processes discussed below may be then employed to produce the desired compound of the invention. Such processes comprise: (a) producing a compound of formula I, which contains bis(CH-OR) groups, in a corresponding compound wherein R is a protecting group. (b) producing a compound of formula I, which contains a mono(CH-OR) group, by selective deprotection in a corresponding compound wherein R is a protecting group. (c) producing a compound of formula I, which contains a CH-OR group, by selective activation of a selected CH-OH group in a corresponding compound wherein -OR is a leaving group which is easUy displaced by nucleophiϋc attack. (d) producing a compound of formula I, which contains a CH-R 100 group, by selective displacement of a selected CH-OR group in a corresponding compound wherein -R 100 is a nucleophile. (e) producing a compound of formula I, which contains a CH-OH group, by selective and final deprotection in a corresponding compound. In process (a), suitable protecting groups for hydroxyl include those groups weU known in the art such as dimethylthexylsilyl, trisubstituted sUyl such as tri(lower)alkylsUyl (e.g. trimethylsUyl, triethylsϋyl, tributylsUyl, tri-i-propylsUyl, tert-butyl-dimethylsUyl, tri-tert- butylsilyl, triphenylmethyl-dimethylsUyl, etc.); lower alkyldiarylsilyl (e.g. methyl- diphenylsilyl, ethyl-diphenylsϋyl, propyl-diphenylsϋyl, tert-butyl-diphenylsilyl, etc.), and the like; triarysilyl (e.g. triphenylsϋyl, tri-p-xylylsilyl, etc.); triarylalkylsϋyl (e.g. tribenzylsUyl, etc.), and the like, in which the preferred one may be tri(Cι-to-C4)alkylsUyl and Cι-to-C4 alkyldiphenylsUyl, and the most preferred one may be tert-butyldimethylsUyl; Suitable o-sUylations may be carried out using a wide variety of organosiϋcon reagents such as, but not ϋmitted to tert-butyldimethylsUyl chloride, N-(tert-butyldimethylsilyl)- N-methyltrifluoroacetamide ( Mawhinney, T., and Madison, M. A. J. Org. Chem., 1982, 47, 3336), tert-butylchlorodiphenylsilane ( Hanessian, S. and Lavallee, P Can. J. Chem., 1975, 63, 2975), tert-butyldimethylsilyl trifluoromethanesulfonate ( Mander, L. Ν. and Sethi, S. P. Tetrahedron Lett., 1984, 25, 5953), dimethylthexylsilyl chloride or dimethylthexylsϋyl trifluoromethanesulfonate (Wetter, H. and Oertle, K. Tetrahedron Lett., 1985, 26, 5515), - l-(tert-butyldimethylsUyl)-imidazole and the like. Carbonate hydroxy-protecting groups may be introduced using a wide variety of a haloformates such as methy, ethyl, 2,2,2-trichloroethyl, isobutyl, vinyl, aUyl, 2-(trimethylsUyl)ethyl, 2-(benzenesuϋ c onyl)ethyl, 2-(tiimethylsUyl)ethoxy methyl, benzyl and substituted benzyl chloroformates, where benzyl substituents include p-methoxy, 3,4-dimethoxy andp-nitro, in the presence of tertiary base such as pyridine, triethylamine, imidazole, diisopropylethylamine and the like. (Tetrahedron Lett., 1980, 21, 3343; ibid., 1981, 22, 3667; ibid. 1981, 22, 969; ibid. 1981, 22, 1933. ) The reaction may be carried out in a solvent which does not adversely affect the reaction (e.g., diethylether, dichloromethane, tetrahydrofuran, chloroform orNN-dimethylformamide or a mixture thereof). The reaction may require cooling or heating, depending on the activation method chosen. Further, the reaction is preferably conducted in the presence of an organic or inorganic base such as an alkaline earth metal (e.g. calcium, etc.), alkaϋ metal hydride (e.g. sodium hydride, etc.), alkaϋ metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaϋ metal hydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkaϋ metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compounds (e.g. pyridine, lutidine, picoϋne, 4-N,N-dimethylaminopyridine, etc.), quinoline, and the like, preferably in the presence of organic bases such as imidazole, triethylamine or pyridine. The reaction may also be carried out using a starting material having an opposite configuration at a carbon center. In this situation, the foUowing two additional steps are required to yield a starting material having an epimeric hydroxyl moiety, i.e. (1) the alcohol is oxidized to its corresponding ketone, (2) the obtained ketone is reduced under selective conditions. Both chiral centers having either [R]- or [S]-configuration can be obtained selectively and separately. In process (b), suitable reagents for selective deprotection of a protecting group from C-32 may be carefully carried out using, but not Umitted to aqueous hydrogen fluoride in acetonitrile (Newton, R. F., Reynolds, D. P., Finch, M. A. W., KeUy, D. R. and Roberts, S. M. Tetrahedron Lett., 1979, 3891), tetraalkyl ammonium fluoride in tetrahydrofuran (Corey, E. J. and Snider, B. B. J. Am. Chem. Soc, 1972, 94, 2549, Corey, E. J. and Venkateswarlu, A. J. Am. Chem. Soc, 1972, 94, 6190) or tetraalkyl ammonium chloride- potassium fluoride in acetonitrile (Carpino, L. A. and Sau, A. C. /. Chem. Soc, Chem. Commun. 1979, 514) whererin an alkyl group as defined above, p-toluenesulfonic acid, potassium carbonate in anhydrous methanol (Hurst, D. T. and Malnnes, A. G. Can. J. Chem., 1965, 43, 2004), citric acid in methanol (Bundy, G. L. and Peterson, D. C. Tetrahedron Lett., 1978, 41), acetic acid : water (3:1) (Corey, E. J. and Varma, R. K. J. Am. Chem. Soc, 1971, 93, 7319), Dowex 50W-X8 in methanol (Corey, E. J., Ponder, J. W. and Ulrich, P. Tetrahedron Lett., 1980, 21, 137), boron trifluoride etherate in chloroform (Kelly, D. R., Roberts, M. S. and Newton, R. F. Synth. Commun. 1979, 9, 295), methanolic hydrogen fluoride (Hanessian, S. and LavaUee, P. Can. J. Chem., 1975, 53, 2975; ibid., 1977, 55, 562), and pyridinuim fluoride in tetrahydrofuran (Nicolaou, K. C, Seitz, S. P., Pavia, M. R. and Petasis, N. A. J. Org. Chem., 1979, 44, 4011), pyridiniump-toluenesulfonate in ethanol (Prakash, C, Saleh, S. and Blair, I. A. Tetrahedron Lett., 1989, 30, 19), N-bromo- succinimide in dimethylsulf oxide (Batten, R.J. et al., Synthesis, 1980, 234), and tetraethyldiboroxane in the presence of catalytic amounts of trimethylsUyl triflate (Dahlhoff, W.V. and Taba, K.M., Synthesis, 1986, 561). The reaction is usually conducted under from cooϋng to heating, preferably from 0 °C to 50 °C. The reaction may require 20 minutes to one day, depending on the reagent and temperature chosen. In process (c), suitable reagents for activation of an alcohol include acetic anhydride, trifluoromethanesulfonic anhydride (triflic anhydride), fluorosulfonic anhydride, methane- sulfonyl chloride (mesyl chloride), p-toluenesulfonyl chloride (tosyl chloride), trifluoroacetic anhydride, trifluoroacetyl chloride, o-nitrobenzenesulfonyl chloride, l-methyl-2-fluoro- pyridinium salt and the like. The activation may be carried out in a solvent which does not adversely affect the reaction (e.g., diethylether, dichloromethane, tetrahydrofuran, chloroform or NN- dimethylformamide or a mixture thereof)- The reaction may require cooling or heating, depending on the activation method chosen. Further, the reaction is preferably conducted in the presence of an organic or inorganic base such as an alkaline earth metal (e.g. calcium, etc.), alkaU metal hydride (e.g. sodium hydride, etc.), alkaϋ metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaU metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaU metal hydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkaϋ metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compounds (e.g. pyridine, lutidine, picoline, 4-N,N-dimethylaminopyridine, etc.), quinoϋne, and the like, preferably in the presence of organic bases such as triethylamine or pyridine. The reaction is usually conducted under from cooling to heating, preferably from -70 °C to 50 °C. The reaction may require 20 minutes to one day, depend on the reagent and temperature chosen. In process (d), a variety of compounds may be prepared from the displacement reactions. An activated hydroxyl group may be reacted with a primary or secondary amine (as defined above and below). The displacement reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. chloroform, dichloromethane, tetrahydrofuran, pyridine, dimethylsulfoxide, NN-dimethylformamide, hexamethylphosphoramide, etc. or a mixture thereof). The reaction may be conducted above, at, or below ambient temperature, preferably from 0 °C to 50 °C. The reaction may require 20 minutes to one week, depend on the reagent chosen. In process (e), a final deprotection of C-24 protecting group may be carried out according to the method described in process (c). The compounds, processes and uses of the present invention wϋl be better understood in connection with the following examples, which are intended as an iUustration of and not a limitation upon the scope of the invention. Both below and throughout the specification, it is intended that citations to the Uterature are expressly incorporated by reference. Example 1: Formula I: Rl Q Ω= H: RJ01= ethyl: RI02= H: Rl = tert-butyldimethylsilyloxy: RlQ4= tgrt-butyldimethylsilyloxy: RI = H. Ascomycin (25 g, 0.032 mol) was dissolved in a solution of imidazole (43.03 g, 0.64 mol) in dry NN-dimemylformamide (500 mL) and tert-butyldimethylchlorosϋane (47.64 g, 0.32 mol) was added in portions and stirred at room temperature for 24 hours. N^-dimethylformamide and excess tert-butyldimethylchlorosUane were removed by evaporation (35 °C water bath ) under high vaccum. The soϋd residue was dissolved in 350 mL of ethyl acetate, and the ethyl acetate layer was washed with saturated ammonium chloride aqueous solution (200 mL x 3), 10 %-ΝaHS04 (200 mL x 3), brine, saturated NaHCO3 (200 mL x 3), and brine (200 mL x 3). After dired over MgSO4, solvent was removed in vacua and the soϋd residue was purified by siϋca gel chromatography, foUowed by HPLC eluting with 5% acetone in hexane providing the title compound (27 g) in 84 % yield. MS (FAB) m/z: M+K = 1058. Example 2 : Formula I: RlΩ Q = H: RJQl^ ethyl: R = H: R = tert-butyldimethylsUyloxy: RlQή= QH: Rjπ = H. To a solution of 48% hydrogen fluoride aqueous solution (5 mL) was added Example 1 (32 g, 0.031 mol) in acetonitrile (500 mL), and the mixture was stirred at room temperature for 90 minutes. It was cooled to 0°C in an ice bath, and solid NaHCO3 was added to the reaction mixture. It was stirred for 1 hour and solid was removed by filtration. Acetonirile was removed in vacua and ethyl acetate (500 mL) was added to tthe residue, and the organic layer was washed with 10%-NaHCO 3 (300 mL x3), brine (250 mL), 10%-NaHSO4 (300 mL x3), and brine ( 350 mL x3), and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 35 g of crude title compound which was purified by sUica gel column chromatography, followed by HPLC eluting with 25%-acetone in hexane. 24.28 g (85 %) of pure compound was obtained. MS (FAB) mlr. M+K = 844; In addition to the title compound, unreacted starting material (Example 1, 1.5 g) and ascomycin (500 mg) were isolated as a pure form. Example 3: Formula I: RiQΩ= H: R-1Q1= ethyl: RlQ2= H: Rifi2=tgrt-butyldimethylsUyloxy: RlQ4=c>-trifluoromethanesulfonyl: RJΩ = H. The product of Example 2 (4.0 g, 4.42 mmol) was dissolved in 20 mL of methylene chloride at 0 °C. pyridine (3.57 mL, 44.2 mmol), followed by trifluoromethanesulfonic acid anhydride (0.74 mL, 4.42 mmol) were carefully added to the reaction mixture. It was stirred at 0 °C for 20 minutes and the solvent was removed. Ethyl acetate (50 mL) was added to the residue. The organic layers were washed with brine, saturated NaHCO3 (20 mL x3), brine (20 mL), 10%-NaHSO4 (20 mL x3), brine (20 mL x3) and dried over anhydrous sodium sulfate. After the solvent was removed, the title compound was obtained in quantitative yield (4.2 g). This compound was used for the displacement reaction without further purification and characterization. Example 4: Formula I: R = H: RlQl= ethyl: Rl Q 2=H: Rl =tert-butyldimethylsilyloxy: The product of Example 3 (2.1 g, 2.03 mmol) was dissolved in 10 mL of freshly distiUed methylene chloride, 1-methylpiperazine (1.24 mL, 10.15 mmol) and triethylamine (0.85 mL, 6.09 mmol) were added, and the reaction was then stirred at 50°C for 5 hours and at room temperature for one over night The reaction mixture was directly poured onto siUca gel column and eluted to obtain semi-pure title compound (925 mg) in 46 % yield. MS (FAB) mlr. M+K = 1026. M+H=988. Example 5: Formula I: RM= H: RJ01= ethyl: Rl02=H: R!Q3=QH: Rl =H: m=0: n=l: The product of Example 4 (920 mg, 0.93 mmol) was dissolved in 10 mL of acetonitrile : water (9 : 1), 48 % hydrogen fluoride aqueous solution [48 %-HF] (0.6 mL) was added, and the reaction was then stirred at room temperature for 5 hours. It was cooled to 0°C in an ice bath, and soϋd NaHCOβ was added to the reaction mixture. It was stirred for 0.5 hour and solid was removed by filtration. Acetoniiile was removed in vacuo and the residue was purified by reverse phase HPLC (RP-HPLC), eluting with acetonitrile-water-0.01% trifluoroacetic acid system. 290 mg of pure title compound was obtained. MS (FAB) mlr. M+H = 874, M+K = 912; mp = 132 oc (dec.) Example 6: Formula I: = H: RM= ethyl: R!02=H: Rl03_=tert-butyldimethylsilyloxy: The product of Example 3 (2.1 g, 2.03 mmol) was dissolved in 8 mL of freshly distiUed methylene chloride, 1-benzylpiperazine (1.06 mL, 6.1 mmol) and triethylamine (0.85 mL, 6.1 mmol) were added, and was then stirred at 45°C for 5 hours. The reaction mixture was directly poured onto siUca gel column and eluted to obtain semi-pure title compound (1.52 g). It was then purified by HPLC, eluting with 30 % acetone-hexane. 660 mg of pure title compound was isolated in 31 % yield. MS (FAB) mlr. M+K = 1102. M+H=1064. Example 7: Formula I: R = H: lfll= ethyl: RlQ2=H: R103=OH: R! =H: m=0: n=l; The product of Example 6 (1.3 g, 1.22 mmol) was dissolved in 35 mL of acetonitrile, 48 % hydrogen fluoride aqueous solution [48 %-HF] (2.2 mL) was added, and the reaction was then stirred at room temperature for 8 hours. The reaction was quenched by the addition of saturated NaHCO3 solution and the product was extracted with 50 mL of ethyl acetate (x2). The ethyl acetate layer was washed with 10%-NaHCO3, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 1 g of crude tile compound was obtained. This was purified by RP-HPLC, eluting with acetonitrile-water-0.01 -trifluoroacetic acid system. 330 mg of the pure title compound was obtained. MS (FAB) mlz: M+H = 950, M+K = 988; mp = 114-116 oc Example 8: Formula I: RM>= H: RlΩ-l= ethyl: Rlfi2=H: RlQ =tert-butyldimethylsilyloxy: R104=H: m=0: n=l: R^R^R^H: Rl=phenyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- phenylpiperazine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-penylpiperazine (1.53 mL, 6.07 mmol), and triethylamine (1.17 mL, 5.05 mmol) in 10 mL of methylene chloride were used. 660 mg of the pure title compound was isolated in 32% yield. MS (FAB) mlz: M+K = 1088. M+H=1050. Example 9: Formula I: Riffik H: RM= ethyl: RJO^H: R-l^=OH: RlΩ4=H: m=0: n=l: Following the procedure of Example 5, the product of Example 8 (250 mg, 0.24 mmol), 48 %- HF (0.5 L) in 10 mL of acetonitrile were used.202 mg of the pure title compound was isolated after purified by RP-HPLC. MS (FAB) mlz: M+K = 974. M+H=936. mp = 119 °C (dec.) Example 10: Formula I: RlΩΩ= H: RJ01= ethyl: R-H =H: RlQ3=tgrt-butyldimethylsilyloxy: FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-tert- butyloxycarbonylpiperazine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-tert-butyloxycarbonylpiperazine (1.13 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 670 mg of the pure title compound was isolated in 31% yield. MS (FAB) mlz: M+K = 1112. M+H=1074. Example 11: Formula I: Rlfl Q = H: RIQ1= ethyl: RJH2=H: R103=OH: RJ04=H: m=0: n=l: Following the procedure of Example 5, the product of Example 10 (660 mg, 0.65 mmol), 48 %-HF (3 mL) in 30 mL of acetonitrile were used. 279 mg of the pure title compound was isolated after purified by RP-HPLC. MS (FAB) mlz: M+K = 998. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-[4- nitrobenzyljpiperazine, provided the desired compound. To a solution of piperazine (2 g, 0.023 mol) in 10 mL of ethanol added a solution of 4-nitrobenzyl bromide (5 g, 0.023 mol) in 20 mL of warm ethanol. It was gently refluxed for 1 hour and stirred at room temperature for one over night. The resulting white precipitate was filtered, washed with a smaU amount of cold ethanol, and dried to yield l-[4-nitrobenzyl]piperazine hydrobromide (3 g). MS mlz M+H = 222, H 1 - NMR (in MeOH-c ) δ = 2.7 (t, 4H, piperazine), 3.25 (t, 4H, piperazine), 3.75 (s, 2H, benzyl), 7.62 (d, 2H, aromatic), 8.20 (d, 2H, aromatic). The obtained l-[4- nitrobenzyljpiperazine hydrobromide (3 g, 9.93 mmol) was dissolved in 60 mL of 3 N sodium hydroxide aqueous solution and stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate (50 mL x 3), and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed to obtain 1.7 g of l-[4- nitrobenzyl]piperazine in 78 % yield. MS mlz M+H = 222, H 1 - NMR (in MeOH-cU) δ = 2.45 (t, 4H, piperazine), 2.90 (t, 4H, piperazine), 3.55 (s, 2H, benzyl), 7.52 (d, 2H, aromatic), 8.50 (d, 2H, aromatic). The product of Example 3 (2.1 g, 2.03 mmol), l-[4-nitrobenzyl]piperazine (1.7 g, 8.1 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45°C for 15 hours. 1.07 g of semi-pure compound was isolated in 48% yield. MS (FAB) mlz: M+K = 1147. M+H=l 109. The obtained product (1.0 g, 0.9 mmol) was treated with 48 %-HF (4 mLj in 30 mL of acetonitrile in the procedure described in Example 5, except stirred at 45 °C for 3 hours. 554 mg of the pure title compound was isolated in 50% yield after RP-HPLC. MS (FAB) mlz: M+K = 1033. M+H=996. mp = 113 °C (dec.) Example 13: Formula I: RlflQ= H: R1ΩL= ethv ι : RIO^ H : RJ03= OH: R1Q4= H: m= 0: n= 1: R3=R^=R≤= H: Rl= β-naphthylmethyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-β-naphthylmethylpiperazine, provided the desired compound. To a solution of piperazine (2.0 g, 0.023 mol) in 15 mL of ethanol added a solution of (2-bromomethyl)naphthalene (5 g, 0.023 mol) in 15 mL of warm ethanol. It was stirred at 55 °C for 1 hour and stirred at room temperature for one over night. The resulting precipitate was filtered, washed with ethyl acetate (20 mL x 2), and dried to yield 1-naphthylmethylpiperazine hydrobromide (2.3 g). MS mlz M+H = 227, H 1 - NMR (in MeOH-d4) δ = 2.85 (t, 4H, piperazine), 3.20 (t, 4H, piperazine), 3.72 (s, 2H, benzyl), 7.45 (m, 3H, aromatic), 7.70 (s, 2H, aromatic), 7.80 (3, 3H, aromatic). The obtained 1-naphthylmethylpiperazine hydrobromide (2.2 g, 7.16 mmol) was dissolved in 50 mL of 3 N sodium hydroxide aqueous solution and stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate (50 mL x 3), and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed to obtain 1.2 g of l-[naphthylmethyl]piperazine in 75 % yield. MS mlz M+H = 227, H 1 - NMR (in MeOH-c ) δ = 2.5 (m, 4H, piperazine), 2.95 (t, 4H, piperazine), 3.55 (s, 2H, benzyl), 7.74 (m, 3H, aromatic), 7.72 (s, 2H, aromatic), 7.79 (m, 3H, aromatic). The product of Example 3 (2.1 g, 2.03 mmol), 1-naphthylmethylpiperazine (1.84 g, 8.1 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 860 mg of pure compound was isolated in 38% yield. MS (FAB) mlz: M+H=l 114. The obtained product (850 mg, 0.76 mmol) was treated with 48 %-HF (4 mL) in 30 mL of acetonitrile in the procedure described in Example 5. 413 mg of the pure title compound was isolated after purified by RP-HPLC in 41% yield. MS (FAB) mlz: M+K = 1038. M+H=1000. mp = 125-126 °C. Example 14: Formula I: R-1ΩQ= H: R!Q1= ethyl: R!02=H: RI0 =QH: RlQ^H: m=0: n=l: R2=R2^R3 ≡ R4 ≡ R5 ≡ H 1 FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with piperidine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), piperidine (0.6 mL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 1.01 g of pure compound was isolated in 55% yield. MS (FAB) mlz: M+H=973. M+K=1011. The obtained product (1.0 g, 1.03 mmol) was treated with 48 %-HF (3 mL) in 40 mL of acetonitrile in the procedure described in Example 5. 560 mg of the pure title compound was isolated in 56% yield. MS (FAB) mlz: M+K = 897. M+H=859. mp = 100-101 °C. Example 15: Formula I: RlΩ Q = H: Rl0J= ethyl: R102=H: RJO^OH: Rl =H: m=0: n=l: R^R^R^H; Rl ^ formyl FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- piperazinecarboxaldehyde, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1 -piperazinecarboxaldehyde (0.62 mL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. It was stirred at 45 °C for 15 hours. 270 mg of pure compound was isolated in 13% yield. MS (FAB) mlz: M+H=1002. M+K=1040. The obtained product (260 mg, 0.26 mmol) was treated with 48 %-HF (1 mL) in 15 mL of acetonitrile in the procedure described in Example 5. 176 mg of the pure title compound was isolated in 68 % yield. MS (FAB) mlz: M+H = 888. M+K=926. mp = 126-128 °C. Example 16: Formula I: RlΩΩ= H: RJ0I= ethyl: RlQ2=H: R103=QH: RJ =H: m=0: n=l: R^R^ ^H: R2 and Retaken together to form -OfCHϊ^O- wherein i = 2. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 4-piperidone ethylene ketal, provided the desired compound. The product of Example 3 (2.0 g, 1.9 mmol), 4-piperidone ethylene ketal (0.742 mL, 5.7 mmol), and triethylamine (0.81 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 1.03 g of pure compound was isolated in 54% yield. MS (FAB) mlz: M+H=1031. M+K=1069. The obtained product (1.0 g, 0.971 mmol) was treated with 48 %-HF (3 mL) in 35 mL of acetonitrile in the procedure described in Example 5. 574 mg of the pure title compound was isolated in 57% yield. MS (FAB) mlz: M+H = 917. M+K=955. mp = 109-110 °C. R^R^R^H: Rl= 2-hvdroxyethyl FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-[2- hydroxyethyljpiperazine, provided the desired compound. The product of Example 3 (2.0 g, 1.9 mmol), l-[2-hydroxyethyl]piperazine (0.71 mL, 5.7 mmol), and triethylamine (0.81 mL, 5.7 mmol) in 10 mL of methylene chloride were used. 970 mg of pure compound was isolated in 49% yield. MS (FAB) mlz: M+H=1018. M+K=1056. The obtained product (960 mg, 0.94 mmol) was treated with 48 %-HF (4 mL) in 40 mL of acetonitrile in the procedure described in Example 5. 414 mg of the pure title compound was isolated in 49% yield. MS (FAB) mlz: M+H = 904. M+K=942. R^R^R^H: X= oxygen Following the procedure of Example 6, but replacing 1-benzylpiperazine with morphoϋne, provided the desired compound. The product of Example 3 (2.0 g, 1.9 mmol), morphoUne (0.51 mL, 5.7 mmol), and triethylamine (0.81 mL, 5.7 mmol) in 10 mL of methylene chloride were used. 780 mg of pure compound was isolated in 42% yield. MS (FAB) mlz: M+H=975. M+K=1013. The obtained product (780 mg, 0.80 mmol) was treated with 48 %-HF (3 mL) in 35 mL of acetonitrile in the procedure described in Example 5. 457 mg of the pure title compound was isolated in 59% yield. MS (FAB) mlz: M+H = 861. M+K=899. mp = 107-108 °C. Example 19: Formula I: RU3Ω= H: RIQ1= ethyl: RJ02=H: R103=OH: RlQ4=H: m=0: n=l: Following the procedure of Example 6, but replacing 1-benzylpiperazine with l-[2-(2- hydroxyethoxy)ethyl]piperazine , provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-{2-(2-hydroxyethoxy)ethyl]piperazine (0.998 mL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 1.2 g of pure compound was isolated in 56% yield. MS (FAB) mlz: M+H=1062. M+K=l 100. The obtained product (1.2 g, 1.13 mmol) was treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, except reaction time was 2.5 hours. 580 mg of the pure title compound was isolated in 53% yield. MS (FAB) mlz: M+H = 948. M+K=986. mp = 102-104 °C. R^R^ ^H- RLS 2-pyridyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-(2- pyridyl)piperazine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), l-(2-pyridyl)piperazine (0.881 mL, 5.79 mmol), and triethylamine (0.81 mL, 5.79 mmol) in 10 mL of methylene chloride are used and stirred at 45 °C for one over night 580 mg of pure compound was isolated after siUca gel column chromatography, foUowed by normal phase HPLC purification in 29% yield. MS (FAB) mlz: M+H=1051. M+K=1089. The obtained product (570 mg, 0.543 mmol) was treated with 48 %-HF (4 mL) in 25 mL of acetonitrile in the procedure described in Example 5, except reaction time was 4 hours. 400 mg - 32 - of the pure title compound was isolated in 63% yield. MS (FAB) mlz: M+H = 937. M+K=975. mp = 110 c (dec). Example 21 : Formula I: M= H: RM= ethyl: R!02=H: R103=QH: R104=H: m=0: n=l: R^R^ ^H; RJ 2-pyrimidyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-(2- pyrimidyl)piperazine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(2-pyrimidyl)piperazine (0.996 mL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. 870 mg of pure compound was isolated after siUca gel column chromatography, foUowed by normal phase HPLC purification in 41% yield. MS (FAB) mlz: M+H=1052. M+K=1090. The obtained product (0.86 g, 0.82 mmol) was treated with 48 %-HF (4 mL) in 30 mL of acetonitrile in the procedure described in Example 5, except reaction time was 3.5 hours. 380 mg of the pure title compound was isolated in 40% yield. MS (FAB) mlz: M+H = 938. M+K=976. mp = 110-111 °C. Example 22: Formula I: RlΩΩ= H: RJ01= ethyl: RJ02=H: R10 =QH: R-1 =H: m=0: n=l: RI ^ R^R^ ^H, Commercially avaUable N-tert-butyloxycarbonyl-piperazine (0.5 g, 2.68 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (0.748 mL, 5.4 mmol), followed by benzyloxycarbonyl chloride (0.575 mL, 3.21 mmol) in diethyl ether was slowly added to the reaction mixture. It was stirred at 0 °C for 1.5 hours. Solvents were removed and 50 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with saturated ΝaHCθ3 (20 mL x 3), brine ( 20 mL x3), and dried over anhydrous sodium sulfate. N-tgrt-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.0 g) was obtained after evaporated to dryness in quantitative yield. MS : M+ΝH4 = 338. M+H + =321. N-tert-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.8 g, 3.13 mmol) was dissolved in 10 mL of 4N-HCl dioxane. It was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, lN-ΝaOH solution was carefuUy added to the mixture to adjust pH above 10. Ethyl acetate (50 mL x3) was used to extract the compound. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate. After removal of the solvent, 1.1 g of Ν-benzyloxycarbonyl-piperazine was obtained in quantitative yield. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with N- benzyloxycarbonyl-piperazine, provided the desired compound. The product of Example 3 (1.1 g, 1.06 mmol), N-benzyloxycarbonyl-piperazine (700 mg, 3.18 mmol), and triethylamine (0.44 mL, 3.15 mmol) in 5 mL of methylene chloride were used. 339 mg of pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-C-24-TBDMS-Ascomycin) was isolated in 29% yield. MS (FAB) mlz: M+H=l 108. M+K=l 146. The above obtained product (329 mg, 0.297 mmol) was treated with 48 %-HF (0.55 mL) in 10 mL of acetonitrile in the procedure described in Example 5. 316 mg of semi pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-Ascomycin) was isolated. This was directly used for the next reaction without further purification. The obtained product (317 mg, 0.32 mmol) was carefuUy hydrogenated in 40 mL of methanol in the presence of 10%-paUadium on charcoal until theoretical ammount of hydrogen gas was consumed. 290 mg of crude product was purified by reverse phase-HPLC. 117 mg of the pure title compound was obtained in 47% yield. MS (FAB) mlz: M+H = 860. M+K=898. mp Example 23: Formula I: RlΩΩ= H: RJΩ1= ethyl: Rl02=H: R103=OH: RI04=H: m=0: n=l; ^R^R^H: R_ = 3-pyridyl. 3-Bromopyridine (0.963 mL, 10 mmol) and piparazine (0.861 g, 10 mmol) are gently refluxed in 20 mL of absolute ethanol until the starting materials are disappeared on TLC. Ethanol is removed in vacua to obtain l-[3-pyridyl]piperazine hydrochloride. The hydrochloride salt is removed according to the procedure described in Example 22 to yield l-[3-pyridyl]piperazine. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-[3- pyridyljpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-[3-pyridyl]piperazine (6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.2 g, 1.13 mmol) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5. The pure title compound is isolated. Example 24: Formula I: RlΩΩ= H: RJ01= ethyl: RJ02=H: R103=OH: RI0 =H: m=0: n=l: R^R^ ^H; Rl= 4-pyridyl. 4-Bromopyridine hydrochloride (2.25 g, 11.61 mmol) and piparazine (5 g, 58.05 mmol) were dissolved in 10 mL of absolute ethanol and replaced into a sealed tube. It was kept in 95°C oU bath for 5 hours and aUowed to stand at room temperature for one over night The white precipitate was filtered off, washed with a smaU amount of cold ethanol, and the filtrate was concentrated in vacuo to obtain l-[4-pyridyl]piperazine hydrobromide hydrochloride salt with a contamination of unreacted piperazine. MS mlz M+H = 165. H 1 - NMR (in CDCI3) δ = 2.95 (m, 4H), 3.36 (t, 4H), 6.82 (2H, aromatic), 8.10 (2H, aromatic). The obtained l-[4- pyridyljpiperazine hydrobromide hydrochloride salt (1.0 g) was dissolved in 50 mL of 3 N sodium hydroxide aqueous solution and stirred at room temperature for 15 minutes. The product was extracted with ethyl acetate (50 mL x3) and the combined ethyl acetate layer was washed with brine ( 50 mL x 2), dried over anhydrous sodium sulfate. The solvent was removed in vacua to obtain 450 mg of l-[4-pyridyl]piperazine in 77 % yield. MS mlz M+H = 165. H 1 - NMR (in CDC1 3 ) δ = 3.00 (m, 4H), 3.30 (t, 4H), 6.65 (2H, aromatic), 8.25 (2H, aromatic). Following the procedure of Example 6, but replacing 1-benzylpiperazine with l-[4- pyridyljpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-[4-pyridyl]piperazine (999 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.2 g, 1.13 mmol) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 25: Formula I: = H: RIΩI= ethyl: R102=H: RlQ3=OH: RJ =H: m=0: n=l: R^R^R^H- R1= methanesulfonyl. N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1 : 1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), foUowed by methanesulfonyl chloride (0.50 mL, 6.44 mmol) in 5 mL of ether were added, and stirred at 0 °C for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL x 3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacua to yield 1.314 g of N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine in 93 % yield. MS mlz M+ΝH 4 = 282. H 1 - NMR (in CDCI 3 ) δ = 1.48 (s, 9H, Boc), 2.79 (s, 3H, S- CH3), 3.18 (t, 4H, piperazine), 3.55 (t, 4H, piperazine). The obtained N-tert- butyloxycarbonyl-N'-methanesulfonyl-piperazine (1.3 g, 4.97 mmol) was dissolved in 10 mL of 20 % trifluoroacetic acid in methylene chloride and stirred at room temperature for 30 minutes. Solvent and trifluoroacetic acid were removed to obtain N-methanesulfonylpiperazine trifluoroacetic acid salt in quantitative yield. MS mlz M+H = 165, H 1 - ΝMR (in MeOH- δ = 2.95 (s, 3H, S-CH3), 3.35 (m, 4H, piperazine), 3.5 (m, 4H, piperazine). The obtained N- methanesulfonylpiperazine trifluoroacetic acid salt (2.2 g) was dissolved in 30 mL of acetonitrile and cooled in an ice bath. Solid sodium bicarbonate was added to the acetonitrile solution and stirred for 2 hours. Solid was filtered off and the filtrate was concentrated in vacua to yield N-methanesulfonylpiperazine in quantitative yield. MS mlz M+H = 165, M+ΝH4 = 182; H 1 - NMR (in MeOH-dL δ = 2.85 (s, 3H, S-CH3), 2.95 (t, 4H, piperazine), 3.22 (t, 4H, piperazine). FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- methanesulfonylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of 1 -methanesulfonylpiperazine (999 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4-mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 26: Formula I: RlΩΩ= H: RJQl^ ethyl: Rlfi2=H: RJQ^OH: RI0 =H: m=0: n=l: R^R^R^H- R 1_ diethylphosphoryl. N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1 : 1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), foUowed by diethylchlorophosphate (1.16 mL, 8.01 mmol) in 5 mL of ether were added, and stirred at 0 °C for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL x 3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacua to yield 1.5 g of N-tert-butyloxycarbonyl-N'-diethylphosphoryl-piperazine in 88 % yield as an oil. MS mlz M+H = 323, M+ΝH4 = 340. H 1 - NMR (in CDCI3) δ = 1.32 (t, 6H, 2 x CH ), 1.48 (s, 9H, Boc), 3.1 (m, 4H, piperazine), 3.37 (t, 4H, piperazine), 4.05 (m, 4H, 2 x OCH 2 ). The obtained N-tert-butyloxycarbonyl-N'-diethylphosphoryl-piperazine (1.5 g, 4.66 mmol) was dissolved in 10 mL of 10 % trifluoroacetic acid in methylene chloride and stirred at room temperature for 30 minutes. Solvent and trifluoroacetic acid were removed to obtain 1.6 g of N-diethylphosphorylpiperazine trifluoroacetic acid salt in quantitative yield. MS mlz M+H = 223, H 1 - ΝMR (in MeOH-cLO δ = 1.35 (m, 6H, 2 x CH 3 ), 3.19 (m, 4H, piperazine), 3.37 (m, 4H, piperazine), 4.05 (m, 4H, 2 x OCH 2 ). FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- diethylphosphorylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of N-diethylphosphorylpiperazine (1.358 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. R^RJ ^ R^H: Rl= 1-pyrrolidinocarbonylmethyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-[1- pyrrolidinocarbonylmethyljpiperazine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), l-[l-pyrrolidinocarbonylmethyl]piperizine (1.14 g, 5.79 mmol), and triethylamine (0.81 mL, 5.79 mmol) in 10 mL of methylene chloride were used. 1.4 g of pure compound was isolated in 67% yield. MS (FAB) mlz: M+H=1085. M+K=1123. The obtained product (1.2 g, 1.11 mmol) was treated with 48 %-HF (4 mL) in 45 mL of acetonitrile in the procedure described in Example 5, except reaction time was 3.5 hours. 620 mg of the pure title compound was isolated in 52% yield. MS (FAB) mlz: M+H = 971. M+K=1009. mp = 110-112 OQ Example 28: Formula I: RH = H: R -= ethyl: Rlfl2=H: R103=QH: R10 =H: m=0: n=l: R^ ^-R^H- Rj- l-morpholinocarbonylmethyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-[1- morpholinocarbonylmethyljpiperazine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), l-[l-morphoϋnoocarbonylmethyl]piperizine (1.23 g, 5.79 mmol), and triethylamine (0.81 mL, 5.79 mmol) in 10 mL of methylene chloride were used. 1.1 g of pure compound was isolated in 55% yield. MS (FAB) mlz: M+H=l 101. The obtained product (1.0 g, 0.909 mmol) was treated with 48 %-HF (4 mL) in 45 mL of acetonitrile in the procedure described in Example 5. 624 mg of the pure title compound was isolated in 56% yield. MS (FAB) mlz: M+H = 987. M+K=1025. mp = 112-113 °C. Example 29: Formula I: RiflΩ= H: RJ Q 1= ethyl: R1Q2=U: R!Q3=QH: Rl =H: m=0: n=l: R^R^R^H: Rl= cvclopropyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- cyclopropylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-cyclopropylpiperazine (6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %- HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^H: Rl= cvclobutyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- cyclobutylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated free base form of 1 -cyclobutylpiperazine (854 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^H- Rl= cvclopentyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- cyclopentylpiperazine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated free base form of 1-cyclopentylpiperazine (934 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. It was gently refluxed at 45 °C for one over night 1.07 g of the title compound with C-24-TBDMS group was isolated in 51 % yield after siUca gel chromatography. MS (FAB) mlz: M+H = 1042. The obtained product (1.05 g, 1.008 mmol) was treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 for 4 hours. After purified by reverse phase HPLC, the pure desirable title compound (459 mg) was obtained in 39 % yield. MS (FAB) mlz: M+K=966. mp = 124-125 °C. R^R^R^-H: RL= cvclohexyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- cyclohexylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated free base form of 1 -cyclohexylpiperazine (1.024 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 33: Formula I: RM= H: RJ& ethyl: Rl02=H: RI03=QH: RI04=H: m=0: n=l: R^R^R^H; Rl= cvcloheptyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- cycloheptylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated free base form of 1-cycloheptylpiperazine (1.110 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to provide the pure title compound. Example 34: Formula I: RlΩΩ= H: RJfl ethyl: RlQ2=H: RIQ3=OH: RIQ4=H: m=0: n=l : R^R^R^H: Rl= cvclooctyl. FoUowing the procedures of Example 6, but replacing 1-benzylpiperazine with 1- cyclooctylpiperazine, provide the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated free base form of 1-cyclooctylpiperazine (1.196 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Exa ple 35: Formula I: Rlfl Q = H: R101= ethyl: R1Q2=H: R103=QH: RJ04=H: m=0: n=l: R^R^ ^H: RJ= N-morpholinocarbonyl. N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1 : 1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by 4- morpholinocarbonyl chloride (0.752 mL, 6.4 mmol) in 5 mL of ether were added, and stirred at 0 °C for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL x 3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacua to yield 1.39 g of N-tert-butyloxycarbonyl-N'-morphoUnocarbonyl-piperazine in 87 % yield as a solid. MS mlz M+H = 300, M+ΝH4 = 317; H 1 - NMR (in CDCI3) δ = 1.49 (s, 9H, Boc), 3.25 (m, 8H, 4 x CH 2 ), 3.52 (m, 4H), 3.65 (m, 4H). The obtained N-tert- butyloxycarbonyl-N'-morpholinocarbonyl-piperazine (1.38 g, 4.62 mmol) was dissolved in 10 mL of 20 % trifluoroacetic acid in methylene chloride and stirred at room temperature for 1 hour. Solvent and trifluoro acetic acid were removed to obtain Ν- morpholinocarbonylpiperazine trifluoroacetic acid salt in quantitative yield. MS mlz M+H = 200, H 1 - ΝMR (in MeOH-cL δ = 3.22 (m, 4H), 3.3 (m, 4H), 3.45 (m, 4H), 3.65 (m, 4H). The obtained N-morpholinocarbonylpiperazine trifluoroacetic acid salt is dissolved in 30 mL of acetonitrile and cooled in an ice bath. Soϋd sodium bicarbonate is added to the acetonitrile solution and stirred for an additional 2 hours. Solid is filtered off and the filtrate is concentrated in vacua to yield Ν-morphoϋnocarbonylpiperazine. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- morpholinocarbonylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-morphoϋnocarbonylpiperazine (1.212 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 36: Formula I: RiΩΩ= H: R1Q1= ethyl: RJ02=H: R103=OH: R!0 =H: m=0: n=l: R ^ R ^ R ^ H - R ^ R ^ OH . Commercially avaUable 4,4-piperidinediol hydrochloride (3.72 g, 20 mmol) is dissolved in 30 mL of acetonitrile and cooled in an ice bath. Solid sodium bicarbonate is added to the acetonitrile solution and stirred for an additional 2 hours. Solid is filtered off and the filtrate is concentrated in vacua to yield 4,4-piperidinediol. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 4,4-piperidinediol, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 4,4-piperidinediol (713.4 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Alternatively, the title compound is also synthesized from the compound of Example 16. Compound of Example 16 (916 mg, 1 mmol) is treated with 10 mL of cold dioxane : HC1 (1 : 1) mixture until starting material is disappeared on TLC plate. The solution is carefuUy evaporated to dryness and purified by reverse phase HPLC as has been described in Example 7. Example 37: Formula I: Rlfl Q = H: R!QL= ethyl: RlQ2=H: RJ03=OH: RJ =H: m=l: n=l: R^R^R^H: Rl= methyl. To a solution of homopiperazine (5 g, 50 mmol) in 10 mL of ethanol added a solution of methyl iodide (0.62 mL, 10 mmol) in 5 mL of ethanol in a sealed tube. It was gently stirred at 95 °C for 5 hours. The resulting white precipitate was filtered, washed with a smaU amount of cold ethanol, and the filtrate was concentrated in vacua to yield 1 -methyl homopiperazine hydroiodide. MS mlz M+H = 115. The obtained 1-methylhomopiperazine hydroiodide is converted into free base according to the procedure describing in Example 25. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1 -methyl homopiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1- methylhomopiperazine (700 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The reaction is carried out at 45 °C for 15 hours. Semi- pure compound is isolated from siϋca gel column chromatography. The obtained product (1.0 g, 0.9 mmol) is treated with 48 %-HF (4 mL) in 30 mL of acetonitrile in the procedure described in Example 5. The pure title compound is isolated from siϋca gel column chromatography, foUowed by reverse phase HPLC. Example 38: Formula I: RlΩ Q = H: RIQ1= ethyl: RJ£2=H; R!^=OH: RlQ4=H: m=0: n=l: R^R^R^H: Rl= piperonyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-piperonylpiperazine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), 1-piperonylpiperazine (1.275 g, 5.79 mmol), and triethylamine (0.81 mL, 5.79 mmol) in 10 mL of methylene chloride were used and stirred at 45 °C for one over night 1.2 g of pure compound was isolated after siUca gel column chromatography, followed by normal phase HPLC purification in 56 % yield. MS (FAB) mlz: M+H=l 108. M+K=l 146. The obtained product (1.2 g, 1.08 mmol) was treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, except reaction time was 5 hours. 702 mg of the pure title compound was isolated in 53 yield after RP-HPLC purification. MS (FAB) mlz: M+H = 994. M+K=1032. mp = 115-117°C. Example 39: Formula I: RlΩΩ= H: RJQ1= ethyl: RJ02=H: R103=OH: RIQ^H: m=0: n=l : R^ ^R^H- R 4-acetylphenyl FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- piperazineacetophenone, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-piperazineacetophenone (1.244 g, 6.09 mmol), and triethylamine (0.563 mL, 4.06 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on siϋca gel cloumn and the compound was eluted with 10 % acetone in hexane to obtain semi-pure product (1.2 g). MS (FAB) mlz : M+K = 1130, M+H = 1092. The obtained product (2.0 g, 1.09 mmol) was treated with 48 %-HF (3 mL) in 30 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure title compound (462 mg) in 43 % yield. MS (FAB) mlz : M+K = 1016. mp = 116-117 °C. Example 40: Formula I: Ri Q Ω= H: RJ01= ethyl: RJ02=H: RIQ =QH: RIQ4=H: m=0: n=l: R^R^R^-H: Ri= (1.3-dioxolane methyl. CommerciaUy avaUable glycerol formal (2.6 mL, 30 mmol) is treated with carbon tetrabromide (11.94 g, 36 mmol) and triphenylphosphine (11.80 g, 45 mmol) in 40 mL of methylene chloride. Fractional distilation gives the desired bromide derivative. The obtained bromo derivative is reacted with piperazine to yield its hydrobromide salt and free base is Uberated by treatment of sotid sodium bicarbonate according to the method described in Example 25. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with the above piparazine derivative, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 3-(l-piperazinyl)-l,3-dioxolanemethyl (1.049 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 41 : Formula I: Ri Q Ω= H: RJ0I= ethyl: R102=H: RJ03=OH: Rl =H: m=0: n=l : FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 3-(l- piperazinyl)-l,2-propanediol, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 3-(l-piperazinyl)-l,2-propanediol (975.7 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 42: Formula I: RiΩ Q = H: RlQl= ethyl: R!02=H RI03=OH: Rl =H: m=0: n=l: R^R^R^H- L 2-pyridylmethyl. CommerciaUy available 2-pyridylcarbinol (2.89 mL, 30 mmol) is treated with carbon tetrabromide (11.94 g, 36 mmol) and triphenylphosphine (11.80 g, 45 mmol) in 40 mL of methylene chloride to obtain 2-pyridylmethyl bromide. The obtained 2-pyridylmethyl bromide is reacted with piperazine to yield its hydrobromide salt, and free base is liberated by treatment of soϋd sodium bicarbonate according to the method described in Example 25. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-[2-pyridylmethyl]piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-[2-pyridylmethyl]piperazine (1.076 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. Pure C-24-TBDMS compound is isolated. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 43: Formula I: Ri Q Ω= H: RJ01= ethyl: RJ02=H: RlQ3=QH: RI0 =H: m=0: n=l: R^R^R -H; R2 an d R^ en together to form -OfCH9)jp- wherein i = 3. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 4-piperidone propylene ketal, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 4-piperidone propylene ketal (975.2 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 44: Formula I: Ri Q Ω= H: R!Q1= ethyl: RlΩ2=H: R10 =OH: Rl =H: m=0: n=l : R^R^ ^H: R2= N-pyrrolidino: R^H. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 4- pyrroUdinopiperidine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), 4-pyrrolidinopiperidine (891 mg, 5.79 mmol), and triethylamine (0.537 mL, 3.86 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 35 °C for 5 hours with stirring. The reaction mixture was purified on siϋca gel cloumn. After the by¬ products were eluted with 10 % acetone in hexane, the compound was eluted with 5 % methanol in methylene chloride to obtain semi-pure product (1.2 g) in 60% yield. MS (FAB) mlz : M+K = 1080, M+H = 1042. The obtained product (1.18 g, 1.13 mmol) was treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. 253 mg (24 %), MS (FAB) mlz : M+K = 928, M+H = 966. mp = 122-125 °C. Ex ple 45: Formula T: RU = H: RJ01= ethyl: Rl Q 2=H: RJ0 =OH: Rl =H: m=0: n=l : R^R^R^H: R2= N-piperidino: R2^=H. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1- piperidinopiperidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1 -piperidinopiperidine (1.025 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^H- R2= N.N-dimethylamino: R2!=H. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 4- dimethylaminopiperidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 4-dimethylaminopiperidine (1.110 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R-CRT H: R =N-pyrrolidinoethyl: R4=R5=H. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 2-(2-N- pyrrolidinoethyl) piperidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 2-(2-N-pyrroϋdinoethyl) piperidine (1.110 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 48: Formula I: R Ω Q = H: R = ethyl: RJ Q 2=H: R103=OH: Rl =H: m=0: n=l: FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 2-(2- dimethylaminoethyl) piperidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 2-(2-dimethylaminoethyl) piperidine (951.7 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Examnle 49: Formula T: RU3 0 = H: R = ethyl: R!02=H: R!Q3=OH: Rl =H: m=0: n=l: R^RI^-H- R^rs N-methyl-2-piperidinomethyl: R^R^-H. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with (S)-N-methyl- 2-[2'-piperidinomethyl]pyrrolidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), (S)-l-methyl-2-(2'-piperidinomethyl)pyιτolidine (1.110 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in \he procedure described in Example 5 to obtain the pure title compound. R^R^H; R3 = (svi-r2-(pyrrolidinomethvm: R =R5=H Following the procedure of Example 6, but replacing 1-benzylpiperazine with (S)-(+)- l-(2-(pyrroϋdinomethyl)pyrrolidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), (S)-(+)-l-(2-(pyrrolidinomethyl)pyrrolidine (939.4 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 51 : Formula I: R 1Ω Q = H: RlΩl= ethyl: RlΩ2=H: R1Ω3=OH: Rl =H: m=0: n=l : Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-(2- piperidylmethyl) dimethylamine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-(2-piperidylmethyl) dimethylamine (866 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 52: Formula I: RlΩ Q = H: RJQ1= ethyl: R102=H: RIO^OH: Rl =H: m=0: n=l : Following the procedure of Example 6, but replacing 1-benzylpiperazine with N,N-diethyl nipecotanide, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N,N-diethyl nipecotanide (1.122 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^H- χ =su if ur . FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with thiomorphoUne, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), thiomorphoUne (1.122 g, 6.09 mmol), and triethylamine (612.5 μL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^-H- R L 3-furoyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with l-(3-furoyl)piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(2-furoyl)piperazine (1.097 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product ( 1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 55: Formula I: RlΩΩ= H: RJQ1= ethyl: R±Q2=H: RlQ =QH: RJ =H: m=0: n=l: R^R^R^H- Rj ^ allyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-allylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of 1-aUylpiperazine (769 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 56: Formula I; R-U&= H: RJΩ1= ethyl: R!02=H: RJ0 =QH: RlΩ4=H: m=0: n=l: R^R^R^H- Rl= propargyl. FoUowing the procedure of Example 6, but replacing 1-benzylpiperazine with 1-propargylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of 1-propargylpiperazine (756 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 57: Formula I: RlΩΩ= H: RJ01= ethyl: R!02=H: RI0 =OH: Rl =H: m=0: n=1 : R^R^R^H: Rl= 2-pyrazinyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(2-pyrazinyl)piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(2-pyrazinyl)piperazine (1.0 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 58: Formula I: RiflΩ= H: RM= ethyl: R1Q2=H: R10 =OH: R104=H: m=0: n=l: Ri R^R^H: R - ethoxycarbonyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 1-ethoxycarbonylpiperazine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-ethoxycarbonylpiperazine (0.889 mL, 6.08 mmol), and triethylamine (0.563 mL, 4.06 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was directly loaded on sUica gel cloumn and the compound was eluted with 20 % acetone in hexane to obtain semi-pure product (952 mg) in 45% yield. MS (FAB) mlz : M+K = 1084, M+H = 1046. The obtained product (900 mg, 0.86 mmol) was treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. 275 mg (34 %), MS (FAB) mlz : M+K = 970, M+H = 932. mp = 110-112 °C. R^R^R^H- R!= ethoxycarbonylmethyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with N-(carboethoxymethyl)piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-(carboethoxymethyl)piperazine (1.049 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 60: Formula I: = H: RJ01= ethyl: RlQ2=H: RI0 =OH: R104=H m =0: n =l ; R^ ^R^H: R = 2-(N.N-diethylamino ethyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-[2-(diethylamino) ethyljpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of l-[2-(dimethylamino) ethyl]piperazine (1.129 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 61 : Formula I: RiΩ Q = H: RJ01= ethyl: Rlfl2=H: R103=QH: RI =H: m=0: n=l: R^R^R^H; Rl= acetyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 1-acetylpiperazine, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-acetylpiperazine (780.6 mg, 6.09 mmol), and triethylamine (0.563 mL, 4.06 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on sϋica gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 20 % acetone in hexane, foUowed by 2.5 % methanol in methylene chloride to obtain product (0.640 g) in 31 % yield. MS (FAB) mlz : M+K = 1054, M+H = 1016. The obtained product (638 mg, 0.629 mmol) was treated with 48 %-HF (3 mL) in 30 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure title compound (394 mg) in 70 % yield. MS (FAB) mlz : M+K = 940, M+H = 902. mp = Example 62: Formula I: Rϋ = H: RJflL= ethyl: Rl02=H: RI0 =QH: RI =H: m=0: n=l: Following the procedure of Example 6, but replacing 1 -benzylpiperazine with isotroperenol, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), base-treated salt free form of isoproterenol (1.07 g, 5.79 mmol), and triethylamine (0.537 mL, 3.86 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on siUca gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 10 % methanol in methylene chloride to obtain semi-pure product (2.1 g). MS (FAB) mlz : M+K = 1111, M+H = 1072. The obtained product (2.0 g, 1.86 mmol) was treated with 48 %-HF (5 mL) in 40 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure title compound (679 mg) in 38 % yield. MS (FAB) mlz : M+K = 997, M+H = 959. mp = 114-118 °C. RI^^R^R^H- R1= N-methyl-N-phenylaminocarbonylmethyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with piperidinoacetic acid N-methylaniUde, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), piperidinoacetic acid N-methylanilide (1.421 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. R^R^R^R^H; R3= N-pyrrolylmethyl FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(2-piperidylmethyl) pyrrole, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of l-(2-piperidylmethyl) pyrrole (1.0 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 65: Formula I: Rl®= H: RlQl= ethyl: RJQ2=H: RIO^OH: RJ =H: m=0: n=l: R^R ^R^R^H; R4= N-pyrrolyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with N-[3-piperidyl]pyrrole, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol) N-[3-piρeridyl]pyrrole (915 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 66: Formula I: R L= H: RJ01= ethyl: R102=H: R1Q _=OH: RlQ4=H: m=0: n=l: FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 4-piperidineethanol, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 4-piperidineethanol (787 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %- HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R2=hvdroxy: R^R^ ^R^H. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 4-hydroxypiperidine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), 4-hydroxypiperidine (0.585 ml, 5.79 mmol), and triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride were used. The obtained product (1.24 g, 65 %, M+H + =989) was treated with 48 %-HF (4 mL) in 40 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound (360 mg) in 33 % yield. MS (FAB) mlz : M+K+ = 913, M+H+ = 875. mp = 98-104 °C. Example 68: Formula I: RJ&L H: R ethyl: R102=H: R103=OH: RI =H: m=0: n=l: FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 4-piperidine carboxamide, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 4-piperidine carboxamide (780.6 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %- HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 69: Formula I: RlΩ Q = H: RJ01= ethyl: R102=H: RJO^OH: RI0 =H: m=0: n=l: R^R^R^R^H- R^ ethoxycarbonyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with ethyl nipecotate, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), ethyl nipecotate (957.4 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 70: Formula I: R-1ΩΩ= H: RJ01= ethyl: R!£2=H: RIQ2=OH: Rl0 =H:m=0: n=l: R^Rf^R^H- R 3-chlorophenyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(3- chlorophenyl) piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of l-(3-chlorophenyl)piperazine (1.198 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 71 : Formula I: R >= H: RJ Q 1= ethyl: RlΩ^H: R103=OH: RI04=H: m=0: n=l: R- R^R^H- R 2-cvanophenyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(2- cyanophenyl) piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(2-cyanophenyl)piperazine (1.140 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 72: Formula I: Ri Q Ω= H: RlOJ= ethyl: R!02=H: R103=QH: R-IQ4=H: m=0: n=l: R^RJ R^H: Rl= 3.4-dimethoxyphenyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(3,4-dimethoxyphenyl) piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of l-(3,4-dimethoxyphenyl)piperazine (1.353 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 73: Formula I: RiΩΩ= H: RJ01= ethyl: Rl02=H: RI03=QH: RlQ4=H: m=0: n=l: R^R^R^H: Rl= 3.4.5-trimethoxyphenyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(3,4,5-trimethoxyphenyl) piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated salt free form of l-(3,4,5-trimethoxy- phenyl)piperazine (1.532 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound. Example 74: Formula I: RiΩΩ= H: RJ01= ethyl: RJΩ2=H: RlQ3=OH: RJ04=H: m=0: n=0: R^R^R^R^-H- R2= acetamido. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 3-acetamidopyrrolodine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 3-acetamidopyrrolodine (780.6 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 75: Formula I: RlΩΩ= H: RJ01= ethyl: RlΩ2=H: R103=OH: RI04=H: m=0: n=0: R ^R^R^R^H- R2= trifluoroacetamido. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 3-[trifluoroacetamido]pyrrolodine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 3-[trifluoroacetamido]pyrrolodine (1.109 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 76: Formula I: RiQQ= H: RJQ ethyl: RlQ2=H: RlQ3=OH: R!04=H: m=0: n=0: R2=R =R4 = R5 = H: R = hvdroxymethyl Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (R)-(-)- 2-pyrrolidine methanol, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), (R)-(-)-2-pyιτolidine methanol (0.571 ml, 5.79 mmol), and triethylamine (0.538 mL, 3.86 mmol) in 10 mL of methylene chloride were used. The obtained product (1.13 g, 60 %, M+H+=989) was treated with 48 %-HF (4 mL) in 30 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound (260 mg) in 27 % yield. MS (FAB) mlz : M+K+ = 913, M+H+ = 875. mp = 90 °C (dec). Example 77: Formula I: RlΩΩ= H: RJΩ1= ethyl: RJ02=H: RI03=OH: RI04=H: m=0: n=l: R^R^R^H; R!= nitro. Piperazine is carefully treated with sodium nitrite and hydrochroUc acid in aqueous media to produce N-nitopiperazine hydrochloride. The obtained N-nitopiperazine hydrochloride (2.2 g) is dissolved in 30 mL of acetonitrile and cooled in an ice bath. Soϋd sodium bicarbonate is added to the acetonitrile solution and stirred for 2 hours. Soϋd is filtered off and the filtrate is concentrated in vacuo to yield N-nitropiperazine. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with 1-nitropiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-nitropiperazine (792.4 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^H- χ =a bsent. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with azetidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), azetidine (410.6 μL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 79: Formula I: RlΩΩ= H: RJQ1= ethyl: R!Q2=H: RI03=OH: Rl =H: m=0: n=0: R^R^R^H- χ = sulfur , FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with thiazolidine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), thiazoϋdine (480.1 μL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 80: Formula I: R Ω Q = H: RJQ1= ethyl: R102=H: RJ03=OH: R10 =H: m=0: n=0: R^R^R^fl. RJ N-aminocarbonylamino FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-imidazolidinyl urea, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-imidazolidinyl urea (792.1 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 81 : Formula I: RlΩ Q = H: RI01= ethyl: R!Q2=H: RIQ2=H: R104=H: m=0: n=l : R^R^R^H; Rl= 2-pyrimidyl. The product of Example 103 (775 mg, 1 mmol) is treated with trifluoromethanesulfonic acid anhydride according to the procedure described in Example 3, and the obtained product is reacted with l-(2-pyrimidyl)piperazine according to the method described in Example 4. The obtained crude product is purified by the method described in example 5 to yield the title compound. Example 82: Formula I: Rl QQ = H: RIQI= ethyl: RU£ and RJ 2 taken together form a bond: R 104=H: m=0: n=l: R^R^R^-H: RJ= 2-pyrimidyl. The product of Example 102 (773 mg, 1 mmol) is treated with trifluoromethanesulfonic acid anhydride according to the procedure described in Example 3, and the obtained product is reacted with l-(2-pyrimidyl)piperazine according to the method described in Example 4. The obtained crude product is purified by the method described in example 5 to yield the title compound. R^R^R^H: Rl= 2-hvdroxyethyl. Compound [Formula I: R 100 = H; R 101 = aUyl; R!0 2 =H; Rl03=OH; R104 =O H; R*05 = H] (25.4 g, 0.0316 mol) is dissolved in a solution of imidazole (43.03 g, 0.64 mol) in dry NN- dimethylformamide (500 mL) and tert-butyldimethylchlorosUane (47.64 g, 0.32 mol) is added in portions and stirred at room temperature for 24 hours. It is then treated in the same fashion described in Example 1 to obtain the compound [Formula I: R 1Q 0= H; R 101 = aUyl; R 102 =H; Rl03 =ter? _b u t idimethylsilyloxy; R 104 =tert-butyldimethylsUyloxy; R 105 = H]. The obtained compound is treated in the same method described in Example 2 to yield the compound [Formula I: R 100 = H; Rl01= aUyl; R 102 =H; Rl03 = -butyldimethylsilyloxy; R!0 =OH; Rl05 = H]. The product of the above reaction (4.1 g, 4.42 mmol) is dissolved in 20 mL of methylene chloride at 0 °C. pyridine (3.57 mL, 44.2 mmol), followed by trifluoromethanesulfonic acid anhydride (0.74 mL, 4.42 mmol) are carefully added to the reaction mixture. It is stirred at 0 °C for 20 minutes and treated in the same procedure described in Example 3 to produce the compound [Formula I: R 100 = H; R 101 = aUyl; R 102 =H; Rl03= te -butyldimethylsilyloxy; Rl04 = o-trifluoromethanesulfonyl; Rl05= H]. The product of the above reaction (2.2 g, 2.03 mmol) is dissolved in 10 mL of freshly distUled methylene chloride, l-[2-hydroxyethyl]piperazine (0.7 ImL, 5.7 mmol) and triethylamine (0.85 mL, 6.09 mmol) are added, and the reaction is then stirred at 50°C for 5 hours and at room temperature for one over night The reaction mixture is treated in the same manner described in Example 6 to produce the compound [Formula I: R l 0 0 = H; R 101 = aUyl; R 102 =H; Rl03 = tø _b U tyidimethylsUyloxy; R 10 =H; R 105 = 4-[2-hydroxyethyl]piρerazinyl]. The product of the above reaction (962 mg, 0.94 mmol) is reacted with 48 % hydrogen fluoride aqueous solution [48 %-HF] by the method described in Example 5 to yield the title compound. Example 84: Formula I: RlΩΩ= H: RJ01= allyl: RJO^H: RI03=OH: RJ =H: m=0: n=l : R^R^R^H- R = 2-pyrimidyl. The title compound is prepared foUowing the procedure of Example 83, but replacing the compound [Formula I: R = H; Rl01= allyl; R Ϊ 0 2 =H; Rl03=OH; Rl0 4 =OH; R 105 = H] with the compound [Formula I: R 1 *^ H; R 101 = methyl; Rl0 2 =H; R^^H; R 1 04=OH; Rl05 = H ]. Example 85: Formula I: Rl QQ = H: RlOJ= methyl: RlΩ 2 =H: R10 =OH: RJQ4=H: m=0: n=l: The title compound is prepared following the procedure of Example 83, but replacing l-[2-hydroxyethyl]piperazine with l-[2-pyrimidyl]piperazine. n=l: R^R^R^H- R 2-hvdroxyethyl. The title compound is prepared foUowing the procedure of Example 83, but replacing the compound [Formula I: R 100 = H; R 101 = aUyl; R 102 =H; R 1 03=OH; R Ϊ O^OH; R 105 = H] with the product of Example 104 , and replacing l-[2-hydroxyethyl]piperazine with l-[2-hydroxyethyl]piperazinyl . Example 87: Formula I: RlΩ Q = H: Rlfll= propyl: RIQ^H: RIQ^OH: RIQ^H: m=0: n=l: R^R^R^H: Rl= 2-pyrimidyl. The title compound is prepared foUowing the procedure of Example 83, but replacing the compound [Formula I: R m = H; R 101 = aUyl; R 102 =H; R!03=OH; R 104 =OH; R 105 = H] with the product of Example 104. Example 88: Formula I: R = H: RJ Q 1= ethyl: RJO^H: RI03=OH: RlQ^H: m=0: n=l; R^R^R^H: RC 3-chloropropyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(3-chloropropyl) piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(3-chloropropyl) piperazine (1.158 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 89: Formula I: RJ QQ = H: R-1Q1= ethyl: RIO^H: RI03=QH: RlOizrH: m=0: n=l: R^R^R^ j- R ; pyrroUdinocarbonylmethyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(pyrroϋdinocarbonylmethyl)piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(pyrroUdinocarbonylmethyl)piperazine (1.201 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 90: Formula I: RJΩ Q = H: RJ01= ethyl: RI02=H: RJ03=OH: R Q^H: m=0: n=l : R^R^R^H: Rl= 2-aminoethyl. l-(2-aminoethyl)piperazine (1.29 g, 10 mmol) is dissolved in 20 mL of dioxane : water (1 : 1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionaUy separated by siUca gel chromatography, foUowed by RP- HPLC to obtain l-[2-tert-butoxycarbonylaminoethyl]piperazine. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-[2-tert- butoxycarbonylaminoethyljpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-[2-tert-butoxycarbonylaminoethyl] piperazine (1.396 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefuUy deprotection of N-tert- butoxycarbonyl group with 10 % trifluoroacetic acid to obtain the pure title compound. Example 91: Formula I: RiΩΩ= H: RJQ1= ethyl: Rl02=H: RIO^OH: RlQ^H: m=0: n=l: R^R^R^H: Rl= N-piperazinoethyl l,l'-ethylenedipiperazine (1.98 g, 10 mmol) is dissolved in 20 mL of dioxane : water (1 : 1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrUe (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionaUy separated by siUca gel chromatography, foUowed by RP- HPLC to obtain N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with N-[4-tert- butoxycarbonylpiperazino]ethyl-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine (1.817 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, foUowed by a carefully deprotection of N-tert- butoxycarbonyl group with 10 % trifluoroacetic acid to obtain the pure title compound. Example 92: Formula I: R L= H: R = ethyl: Rl02=H: R10 =OH: RIQ^H: m=0: n=0: Following the procedure of Example 6, but replacing 1 -benzylpiperazine with proUne, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), proline (700 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrUe in the procedure described in Example 5 to obtain the pure title compound. Example 93: Formula I: RlΩΩ= H: RlΩl * = ethyl: RJO^H: R103=OH: RJO^H: m=0: n=l : R^R^R^H; R!= 2-cvclohexylethyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-[2-cyclohexylethyl] piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-[2-cyclohexylethyl] piperazine (1.195 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrUe in the procedure described in Example 5 to obtain the pure title compound. Example 94: Formula I: RlΩΩ= H: RJ01= ethyl: R-IQ^H: RI0 =OH: RIO^H: m=0: n=l: l-(2-[3-pyridylmethylamino]-ethyl)-piperazine (2.20 g, 10 mmol) is dissolved in 20 mL of dioxane : water (1 : 1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by siϋca gel chromatography, foUowed by RP-HPLC to obtain l-(2-[N-tert-butoxycarbonyl-3- pyridylmethylamino]-ethyl)-piperazine. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(2-[N-tert- butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(2-[N-tert-butoxycarbonyl- 3-pyridylmethylamino]-ethyl)-piperazine (1.951 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, foUowed by a carefuUy deprotection of N-tert-butoxycarbonyl group with 10 % trifluoroacetic acid to obtain the pure title compound. Example 95: Formula I: RiΩ0= H: RlQl= ethyl: RJO^H: RlQ3=QH: RIO^H: m=l: n=l: R^R^R^H- R 3-chloropropyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(3- chloropropyl)homopiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(3-chloropropyl)homopiperazine (1.021 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. R^R^R^H: Rl= 5-iodonaphthalene-l-sulfonyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with l-(5- iodonaphthalene-l-sulfonyl)-lH-hexahydro-l,4-diazepine , provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), l-(5-iodonaphthalene-l-sulfonyl)-lH- hexahydro-l,4-diazepine (2.535 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 97: Formula I: Rl = H: RJQ1= ethyl: RJO^H: RJ03=OH: RJO^H: m=2: n=l: R2^2^=RU=R5^ FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with heptamethyleneimine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), heptamethyleneimine (769 μL, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48 %- HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 98: Formula I: Rl Q Ω= H: RJQ1= ethyl: RlQ^H: R10 =OH: RI and Rl taken together form an oxo group. Methylsulfide-chlorine complex was prepared by adding oxalyl chloride (0.32 g) into a stirred solution of dimethylsulfoxide (0.44 g) in methylene chloride (4 mL) and stirring at -70 °C for 0.5 hours. The solution of the complex was added in slow dropwise fashion into a stirring solution of ascomycin (1.6 g) in methylene chloride (5 mL) at -70 °C. After stirring for 0.25 hours, triethylamine (1.4 g) was added at -70 °C. Stirring was continued at -70 °C for 0.5 hours and then at room temperature for 1 hour. The reaction mixture was then dUuted with ether (100 mL), washed with 1 N HC1 (aq) (2x30 mL), saturated brine (30 mL), dried over magnesium sulfate and solvent removed. The product was purified on sUica gel (70 g) with ether elution. Yield: 0.95 g; MS (FAB) mlz: M+H = 790. Lithium tri-t-butoxyaluminum hydride (0.2 mL, 1 M in THF) was added slowly into a stirred solution of the product of Example 48 (0.056 g) in dry THF (1 mL) at -70 °C under nitrogen. After stirring at -70 °C for 3 hours, it was partitioned between ether (50 mL) and 1 N HC1 (10 mL). The organic phase was dried over magnesium sulfate, the solvent was removed and the product purified by prep TLC (35% acetone in hexanes). Yield: 0.025 g; MS (FAB) mlz: M+K = 830. trifluoromethanesulfonyl. The product of Example 99 (4.0 g, 4.42 mmol) is dissolved in 20 mL of methylene chloride at 0 °C. pyridine (3.57 mL, 44.2 mmol), followed by trifluoromethanesulfonic acid anhydride (0.74 mL, 4.42 mmol) are carefuUy added to the reaction mixture. It is stirred at 0 °C for 20 minutes and the solvent is removed. Ethyl acetate (50 mL) is added to the residue. The organic layers are washed with brine, saturated NaHCO3 (20 mL x3), brine (20 mL), 10%-NaHSO4 (20 mL x3), brine (20 mL x3) and dried over anhydrous sodium sulfate. After the solvent is removed, the title compound is obtained. This compound was used for the displacement reaction without further purification and characterization. Example 101 Formula I: Ri Q Ω= H: RJΩI= ethyl: RJΩ^H: R103=QH: m=0: n=l: R^R^ ^H- R methyl: R_ms=H. The product of Example 100 (2.1 g, 2.03 mmol) is dissolved in 10 mL of freshly distilled methylene chloride, 1-methylpiperazine (1.24 mL, 10.15 mmol) and triethylamine (0.85 mL, 6.09 mmol) are added, and the reaction is then stirred at 50°C for 5 hours and at room temperature for one over night. The reaction mixture is directly poured onto siUca gel column and eluted to obtain pure title compound. Example 102.: Formula I: R >= H: RJfll= ethyl: R!Q2- and RJ taken together form a bond: Ascomycin (10 g, 12.6 mmol) and pyridinium p-toluene sulfonate (1 g, 3.98 mmol) were dissolved in 200 mL of toluene and stirred at 70 °C for one over night. Solvent was removed and the residue was purified by siUca gel column chromatography, eluting with 5-10% acetone in hexane. 8.89 g of the title compound was isolated in 91 % yield. MS (FAB) mlz: M+K = 812. Example 103 : Formula I: M= H: R!Ω1= ethyl: Rl02=H: R!0 =H: RJO^QH: R!05=H. The product of Example 102 (2.2 g, 2.8 mmol) was hydrogenated in the presence of 5% rhodium on alumina (220 mg) in 100 mL of ethanol at room temperature for 1 hour. After filtered, the filtrate was concentrated in vacuo to obtain the title compound in quantitative yield. The obtained product was then loaded on siϋca gel column, and eluted with 5-10% acetone in hexane to obtain the pure title compound in 75-80 yield. MS (FAB) mlz: M+K = 814. RI05=R FK-506 (150 mg, 0.2 mmol) was dissolved in 6 mL of ethyl acetate and 30 mg of 10%- palladium on charcoal was added. It was hydrogenated at room temperature for 20 minutes under one atmosphere pressure. After filtered the catalyst, the solvent was evaporated to dryness to yield 150 mg of crude product which was then purified by silica gel column chromatography, eluting with chloroform : acetone (5 : 1) mixture. 114 mg of the pure title compound was isolated in 76% yield. MS (FAB) mlz: M+K = 844. Example 105: Formula I: RlΩΩ= H: RJΩ1= ethyl: RlO^H: RIQ =0H: RIQ^H: m=0: n=l: R 2 =R 2 ^=R 4 =R5 = H: R3= hvdroxymethyl. Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (+/-)-2- piperidinemethanol, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), (+/-)-2-piperidinemethanol (700 mg, 6.08 mmol), and triethylamine (0.846 mL, 6.08 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on sUica gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 10 % methanol in methylene chloride to obtain the product (850 mg) in 42 % yield. MS (FAB) mlz : M+K = 1041, M+H = 1003. The obtained product (850 mg, 0.85 mmol) was treated with 48 %-HF (3.5 mL) in 35 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure title compound (290 mg) in 39 % yield. MS (FAB) mlz : M+K = 927, M+H = 889. mp = 98-100 °C. Example 106: Formula I: R = H: R = ethyl: RlQ^H: RI02=OH: RJ≤ =H: m=0: n=l: R 2 =R 2 ^R3 = R5 = H; R4= hvdroxymethyl. Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (+/-)-3- piperidinemethanol, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), (+/-)-3-piperidinemethanol (700 mg, 6.08 mmol), and triethylamine (0.846 mL, 6.08 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on siϋca gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 10 % methanol in methylene chloride to obtain the product (1.34 g) in 66 % yield. MS (FAB) mlz : M+K = 1041, M+H = 1003. The obtained product (1.34 g, 1.33 mmol) was treated with 48 %-HF (4 mL) in 40 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure tide' compound (247 mg) in 20 % yield. MS (FAB) mlz : M+K = 927, M+H = 889. mp = 110-112 oQ Example 107: Formula I: R = H: RJfli= ethyl: Rl02=H: RIO^QH; RIQ^H: m=0: n=l: R 2 =R 2 ^R4 = R5 = H: R = 2-hvdroxyethyl. FoUowing the procedure of Example 6, but replacing 1 -benzylpiperazine with (+/-)-2- piperidine-ethanol, provided the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), (+/-)-3-piperidine-ethanol (785 mg, 6.08 mmol), and triethylamine (0.0.846 mL, 6.08 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on siUca gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 10 % methanol in methylene chloride to obtain the product (1.32 g) in 64 % yield. MS (FAB) mlz : M+H = 1017. The obtained product (1.3 mg, 1.28 mmol) was treated with 48 %-HF (4 mL) in 40 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure title compound (615mg) in 53 % yield. MS (FAB) mlz : M+K = 941, M+H = 903. mp = 85-90 °C. Example 108: Formula I: R±&-= H: R101= ethyl: Rl02=H: RI0 =OH: JO^H: m=0: n=l: R =R2:=R3 = R5 = H; R4= hvdroxy. Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (+/-)-3- hydroxypiperidine, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), (+/-)-3-hydroxypiperidine(0.585 ml, 5.79 mmol), and triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on sUica gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 10 % methanol in methylene chloride to obtain the product (1.11 g) in 58 % yield. MS (FAB) mlz : M+H = 989. The obtained product (1.10 g, 1.113 mmol) was treated with 48 %-HF (4 mL) in 40 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure title compound (149 mg) in 15 % yield. MS (FAB) mlz : M+K+ = 913, M+H+ = 889. Example 109: Formula I: Rl QQ = H: RlQl= ethyl: Rl^=H: R103=OH: RJO^H: m=0: n=l: R 2 =R 2 ^R4 = R5 = H: R = hvdroxymethyl. Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (S)-(+)-2- pyrrolidine methanol, provided the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), (S)-(+)-2-pyrroϋdine methanol (0.571 ml, 5.79 mmol), and triethylamine (0.538 mL, 3.86 mmol) in 10 mL of methylene chloride were used. The reaction was carried out at 45 °C for one over night with stirring. The reaction mixture was purified on siϋca gel cloumn. After the column was washed with 10 % acetone in hexane to remove by-products, the compound was eluted with 10 % methanol in methylene chloride to obtain the product (1.24g) in 65 % yield. MS (FAB) mlz : M+H = 989. The obtained product (1.04 g, 1.06 mmol) was treated with 48 %-HF (4 mL) in 40 mL of acetonitrile and then purified in the procedure described in Example 5 to obtain the pure tide compound (212 mg) in 23 % yield. MS (FAB) mlz : M+K + = 913, M+H+ = 875. mp = 75-95 °C. . Example 1 \0(Ά): Formula I: R ΩΩ= H: R!Q1= ethyl: R1£2=H: Ri03=Rl04=dimethylthexylsilyloxy: R!Q5=H: Ascomycin (1 g, 1.26 mmol) was dissolved in a solution of imidazole (0.86 g, 12.6 mmol) in dry NN-dimethylformamide (10 mL) and dimethylthexylchlorosilane (1.24 g, 6.3 mmol) was added in portions and stirred at room temperature for 3 days. Diethylether (100 ml) was added to the reaction mixture, and the organic layer was washed with saturated ammonium chloride aqueous solution (30 mL x 3), 10 %-ΝaHS04 (30 mL x 3), brine (30 mL), saturated NaHCO3 (30 mL x 3), and brine (30 mL x 3). After dired over MgSO4, solvent was removed in vacuo and the solid residue was purified by siUca gel chromatography (569 mg), foUowed by HPLC eluting with 10% acetone in hexane providing the tide compound (372.5 mg) in 27 % yield. MS (FAB) mlz: M+K+ = 1114. mp = 100-104 °C Example 110(b : Formula I: Ri Q Ω= H: RM= ethyl: RJO^H: RJ03=OH: During the purification of the crude product of Example 110-(a) by siUca gel column chromatography, pure-mono substituted tide compound (456 mg) was isolated in 39 % yield MS (FAB) mlz: M+K+ = 972. mp = 92-94 °C Example 111: Formula I: RiΩ Q = H: RlQl= ethyl: R±Q2= H: R!Q2= dimethylthexylsUyloxy: RJ04= QH: Rm = H. To a solution of 48% hydrogen fluoride aqueous solution (0.2 mL) was added Example 110- (a) (0.2 g, 0.186 mmol) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 30 minutes. It was cooled to 0°C in an ice bath, and solid NaHCO3 was added to the reaction mixture. It was stirred for 1 hour and solid was removed by filtration. Acetonitrile was removed, and the crude tide compound was purified by siϋca gel column chromatography. 140 mg (81 %) of pure compound was obtained. MS (FAB) mlz: M+K = 972. Example 112: Formula I: R^= H: RlQl= ethyl: R±Q2= H: RJΩ2= OH: RJ = H: m= 1: n= 0: R2 and R^ taken together = CH2: Rl= benzyl: R = H. Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (1S,4S)- 2-benzyl-2,5-diazabicyclo[2.2.1]heptane, provides the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), (lS,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane (1.09 g, 5.79 mmol), and triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride are used. The obtained product is treated with 48 %-HF (4 mL) in 40 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 113: Formula I: Rϋ&= H: R = ethyl: R!Q2= H: R!^= OH: RIQ 4 = H: m= 1: n= 0: R2 and R^ taken together = CH2: R = H: X= oxygen Following the procedure of Example 6, but replacing 1 -benzylpiperazine with (lS,4S)-2-oxa- 5-azabicyclo[2.2.1]heptane, provides the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (587 mg, 5.79 mmol), and triethylamine (0.538 mL, 3.86 mmol) in 10 mL of methylene chloride are used. The obtained product is treated with 48 %-HF (4 mL) in 30 mL of acetonitrile in the procedure described in Example 5 to obtain the pure tide compound. Example 114: Formula I: Ri QQ = H: R-1Q1= ethyl: R 102= H: RJQ = QH: R!Q = H: m= 1 : n= 0: R^ and R^ = H: X= oxygen: R^= N.N-dimethylaminomethyl. 2-[(N,N-dimethylamino)methyl]mo holine is prepared by the method described in the literature (Araki, K. et. al, J. Med. Chem. 36:1356-1363 (1993)). Following the procedure of Example 6, but replacing 1 -benzylpiperazine with 2-[(N,N-dimethylamino)methyl]- morpholine, provides the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), 2-[(N,N-dimethylamino)methyl]morpholine ( 5.79 mmol), and triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride are used. The obtained product is treated with 48 %- HF (4 mL) in 40 mL of acetonitrile in the procedure described in Example 5 to obtain the pure title compound. Example 115: Formula I: = H: RI01= ethyl: RlQ2= H: R = QH: Rl = H: m= 1 : n= 0: R^ and R^ = H: X= oxygen: R = 2-acetamidoethyl. 2-(2-Acetamidoethyl)morphoϋne is prepared by the method described in the Uterature (Araki, K. et. al., J. Med. Chem. 36:1356-1363 (1993)). Following the procedure of Example 6, but replacing 1 -benzylpiperazine with 2-(2-acetamidoethyl)morpholine, provides the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), 2-(2-acetamidoethyl)morphoUne (5.79 mmol), and triethylamine (0.538 mL, 3.86 mmol) in 10 mL of methylene chloride are used. The obtained product is treated with 48 %-HF (4 mL) in 30 mL of acetonitrile in the procedure described in Example 5 to obtain the pure tide compound. R^ and R^ = H: X=oxygen: R^=2-r(ethoxycarbonyl'>amino1methyl. 2- { [(Ethoxycarbonyl)amino] methyl Jmorpholine is prepared by the method described in the literature (Araki, K. et. al., J. Med. Chem. 36:1356-1363 (1993)). FoUowing die procedure of Example 6, but replacing 1 -benzylpiperazine with 2- {[(ethoxycarbonyl)amino] methyl }- morphoϋne, provides the desired compound. The product of Example 3 (2.0 g, 1.93 mmol), 2-{ [(ethoxycarbonyl)amino]methyl}morphoUne ( 5.79 mmol), and triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride are used. The obtained product is treated with 48 %-HF (4 mL) in 40 mL of acetonitrile in the procedure described in Example 5 to obtain the pure tide compound. Example 117: Formula I: RJ Q Q = OH: RlQl= ethyl: Rl02=H: RI03=H: RJO^ H: m= 0: n= l; R^R^R = H: RL= 2-pyrimidyl. The product of Example 81 (5 mmol) is dissolved in 25 mL of methylene chloride. This is added to a solution of 5 mL of methylene chloride containing tert-butyl hydroperoxide in 2,2,4-trimethylpentane (6.65 mL, 20 mmol) and selenium oxide (830 mg, 7.5 mmol). The reaction is monitored by thin layer chromatography. The mixture is stirred at room temperature until the starting material is disappeared. Solvents are removed and an approximately 100 mL of ethyl acetate is added to the residue. The ethyl acetate layer is washed with brine, dried over anhydrous sodium sulfate. Purification of the title compound is carried out by high performance liquid chromatography. Example 118: Formula I: RlQO = F: R!Q = ethyl: RJO^H: RJQ3=H: RIQ4=H: m= 0: n= 1: R^R^R^ H: Rl= 2-pyrimidyl. A solution of the product of example 117 (100 mg) in 1 mL of methylene chloride is cooled to -78 °C in a dry ice/isopropanol bath. To this stirred solution, diethylaminosulfur trifluoride (10 μL) is added. After 3 minutes, saturated sodium bicarbonate ( ImL) is added followed by 5 mL of ethyl acetate and the mixture is warmed to room temperature. Extraction from ethyl acetate, drying over anhydrous magnesium sulfate and purification by high performance Uquid chromatography gives the pure title compound. Example 119: Formula I: R I = OαOlOft: R- = ethyl: R Ω = H: H&= H: Rl = H: m= 0: n= 1: R3=R4=R5 = H: R!= 2-pyrimidyl. A solution of the product of example 117 (100 mg) in 1 mL of pyridine is cooled to 0 °C in an ice bath. To this stirred solution, N,N-dimethylaminopyridine (3 μg), followed by acetic acid anhydride (20 μl) are added. After stirred at 0 °C for 5 hours, it is stirred at room temperature for one over night Extraction from ethyl acetate, drying over anhydrous magnesium sulfate and purification by high performance Uquid chromatography gives the pure title compound. Example 120: In Vitro Assay of Biological Activity The immunosuppressant activity of the compounds of the present invention was determined using the human mixed lymphocyte reaction (MLR) assay described by Kino, T. et al. in Transplantation Proceedings XIX(5):36-39, Suppl. 6 (1987), incorporated herein by reference. The results of the assay, shown below in Table 1, demonstrate that the compounds tested are effective immunomodulators at sub-micromolar and, in some instances, sub- nanomolar concentrations. Table 1 It is understood that the foregoing detailed description and accompanying examples are merely Ulustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by die appended claims and their equivalents. Various changes and modifications to the disclosed embodiments wiU be apparent to those skiUed in the art Such changes and modifications, including widiout limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims: What is claimed is: 1. A compound having the formula or a pharmaceuticaUy acceptable salt ester, amide or prodrug thereof, wherein R 100 is selected from the group consisting of hydrogen, hydroxy, halogen, -OR 13 a nd -OR 14 ; R 101 is selected from die group consisting of methyl, ethyl, aUyl and propyl; R 102 i s hydrogen and R 10 is selected from the group consisting of (a) hydrogen, (b) hydroxyl and (c) hydroxyl protected by a hydroxy-protecting group or, taken together, Rl° 2 and Rl° 3 form a bond; and one of RIO 4 and Rl05 i s hydrogen, and the other of R O 4 and R 5 i s a group having the formula where m and n are independentiy zero, one or two; X is selected from the group consisting of oxygen, -S(O) s - where s is zero, one or two, -N(Rl)- and -C(R 2 )(R 2' )-, or is absent; and R3, R 4 and R^ are independentiy selected from the group consisting of (a) hydrogen; (b) alkyl; (c) haloalkyl; (d) cycloalkyl; (e) cycloalkylalkyl; (f) alkenyl; (g) alkynyl; (h) hydroxyalkyl; (i) hydroxylalkoxyalkyl; (j) aryl substituted by R 6 , R 7 and R 8 ; (j') arylalkyl substituted by R 6 , R 7 and R 8 ; (k) alkoxycarbonyl; (1) alkoxycarbonylalkyl; (m) carboxyalkyl; (n) aminoalkyl; (o) thiolalkyl; (p) acyl; (q) heterocycUc; (r) (heterocyclic)alkyl; (s) (heterocyclic)alkylaminoalkyl; (u) N-monoalkylaminoalkyl; (u 1 ) N,N-dialkylaminoalkyl; (v) N-monoalkylcarboxamidoalkyl; (v') N,N-dialkylcarboxamidoalkyl; (w) N-monoarylcarboxamidoalkyl; (w 1 ) N,N-diarylcarboxamidoalkyl; (x) formyl; (x') protected formyl; (z) (heterocycUc)alkenyl; and (aa) (heterocycϋc)alkynyl; or, taken together, R 3 and R 5 form a methylene radical -CH 2 -; R 1 is selected from the group consisting of (a) hydrogen; (b) alkyl; (c) haloalkyl; (d) cycloalkyl; (e) cycloalkylalkyl; (f) alkenyl; (g) alkynyl; (h) hydroxyalkyl; (i) hydroxyl-alkoxyalkyl; (j) aryl substituted by R 6 , R 7 and R 8 ; (j') arylalkyl substituted by R 6 , R 7 and R 8 ; (k) alkoxycarbonyl; (1) alkoxycarbonylalkyl; (m) carboxyalkyl; (n) aminoalkyl; (o) thiolalkyl; (p) -S(O) x -R 9 where x is one or two and R^ is selected from the group consisting of alkyl, aryl, and arylalkyl; (p') acyl; (q) heterocycUc; (r) (heterocyclic)alkyl; (s) (heterocyclic)alkylaminoalkyl; (u) N-monoalkylaminoalkyl; (u 1 ) N,N-dialkylaminoalkyl; (v) N-monoalkylcarboxamidoalkyl; (v') N,N-diaU ylcarboxamidoalkyl; (w) N-monoarylcarboxamidoalkyl; (w 1 ) N,N-diarylcarboxamidoalkyl; (x) formyl; (x') protected formyl; (y) -P(O)(OR 10 )(OR 10' ) where R 10 and R 10' are independentiy selected from the group consisting of loweralkyl, arylalkyl and aryl; (z) (heterocycUc)alkenyl; (aa) (heterocycUc)alkynyl; (bb) urea; (cc) nitro; and (dd) polyhydroxylalkyl; R 2 and R 2 ' are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amidoalkyl, N-alkylcarboxamido, N,N-dialkylamino, and where m' is an integer selected from four and five; or, taken together, R 2 and R 2' are a divalent radical selected from the group consisting of oxo, thiooxo or -O(CH 2 )iO-, where i is two, three or four; Ro, R 7 and R 8 are independentiy selected from the group consisting of (i) hydrogen; (ii) -(Cι-to-C 7 alkyl); (iϋ)-(C 2 -to-C6 alkenyl); (iv) halogen; (v) -(CH2) m ΝR 11 R 11' where m is an integer between one and ten, and R 11 and R 11' are independentiy selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heterocycUc, (heterocycϋc)alkyl, (heterocycϋc)alkenyl and (heterocy ic)alkynyl; (vi) -CN; (vii) -CHO; (viϋ) mono-, di-, tri- or perhalogenated alkyl; (ix) -S O^R 11 where s is zero, one or two; (x) -C(O)NR 11 R 11' ; (xi) -(CH2) m ORll; (xii) -CH(OR 12 )(OR 12' ), where R 12 and R 12' are independently -(Cι-to-C 3 alkyl) or, taken together, form an ethylene or propylene bridge; (xiϋ) -(CH 2 ) m OC(O)R 11 ; (xiv) -(CH 2 ) m C(O)OR 11 ; (xv) -OR 13 , where R 13 is selected from the group consisting of (A) -PO(OH)O-M+, (B) -SO -M+, and (C) -C(O)(CH 2 ) m C(O)O-M+, where M + is a proton or a positively charged inorganic or organic counterion; (xvi) -S^ t NR^R 11' , where t is one or two; (xvii) -NO 2 ; (xvni) -N3; and (xviv) guanidino optionaUy substituted by a radical selected from the group consisting of loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and alkylsulfonyl, or any two adjacent R 6 , R 7 and R 8 and the atoms to which they are attached form a carbocycUc or heterocyclic ring having between 5 and 7 ring atoms which includes up to two additional heteroatoms independently selected from the group consisting of -O-, -S(O) s - where s is zero, one or two, and -NR 11 -; and RI 4 is selected from the group consisting of (i) acyl ; (n) -(Cι-to-θ7 alkyl); (iii) -(C 2 -to-C 6 alkenyl); (vi) -(CH^mNR^R 11' , where m is an integer between one and ten; (v) -S(O) s R 11 , where s selected from the group consisting of zero, one and two; (vi) -C^NR ii R 11 '; (vii) -(CH^mOR 11 ; (vϋi) -CH(OR 12 )(OR 12' ); (ix) -(CH^OC^R 11 ; (x) -(CH 2 ) m C(O)OR π ; and (xi) -S(O) t NR 11 R 11' , where t is selected from the group consisting of one and two. 2. A compound according to Claim 1 wherein R 100 is hydrogen. 3. A compound according to Claim 1 wherein R 101 is ethyl. 4. A compound according to Claim 1 wherein R 102 is hydrogen. 5. A compound according to Claim 1 wherein R 103 is selected from the group consisting of hydrogen and hydroxyl. 6. A compound according to Claim 1 wherein R 103 is hydroxyl protected by a hydroxy-protecting group. 7. A compound according to Claim 1 wherein R 104 is hydrogen. 8. A compound according to Claim 1 wherein m and n are integers independentiy selected from the group consisting of zero and one. 9. A compound according to Claim 1 wherein R 105 is a radical having the formula 10. A compound according to Claim 9 wherein X is selected from the group consisting of -S(O) s - , -C(R 2 )(R 2' )- and -NfR 1 )-. 11. A compound according to Claim 9 wherein R 1 , R 3 , R 4 and R 5 are independently selected from the group consisting of (a) hydrogen; (b) alkyl; (c) cycloalkyl; (d) cycloalkylalkyl; (e) hydroxyalkyl; (f) hydroxyl-alkoxyalkyl; (g) aryl substituted by R 6 , R 7 and R 8 ; (h) arylalkyl substituted by R 6 , R 7 and R 8 ; (i) alkoxycarbonyl; (j) alkoxycarbonylalkyl; (k) carboxyalkyl; (1) aminoalkyl; (m) thiolalkyl; (n) heterocycUc; (o) (heterocycUc)alkyl; (p) (heterocycUc)alkylaminoalkyl; (q) acyl; (r) N-mono- or N,N-dialkylaminoalkyl; (s) N-mono- or N,N-dialkyl-carboxamidoalkyl; (t) N-mono- or NN-diarylcarboxamidoalkyl; and (u) formyl. 12. A compound according to Claim 9 wherein X is selected from the group consisting of -N(R l )- and -C(R 2 )(R 2 ')-. 13. A compound according to Claim 9 wherein the total of the integers m and n is an integer selected from the group consisting of zero, one and two. 14. A compound selected from the group consisting of the compounds described in Examples 5, 7, 9, 11-22, 27, 28, 31, 38, 39, 44, 58, 61, 62, 67, 76 and 105-111 herein, or a pharmaceuticaUy acceptable salt, ester, amide or prodrug thereof. 15. A pharmaceutical composition, comprising a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier. 16. A pharmaceutical composition, comprising a compound according to Claim 14 in combination with a pharmaceuticaUy acceptable carrier. 17. A method for treating a patient in need of immunomodulative therapy, comprising administering to said patient a therapeuticaUy effective amount of a compound according to Claim 1. 18. A method for treating a patient in need of immunomodulative therapy, comprising administering to said patient a therapeuticaUy effective amount of a compound according to Claim 14.

Inventors: KAWAI MEGUMI, LULY JAY R, KAWAI, MEGUMI, LULY, JAY, R.
Applicants: ABBOTT LAB, ABBOTT LABORATORIES
Application year: 1994
Main classification: A61K31
IPC codes: A61K31, A61P37, C07D498